STREPTOCOCCUS PNEUMONIAE: VIRULENCE FACTORS AND THEIR ROLE IN PATHOGENESIS.

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Streptococcus pneumoniae

Ukpai A. Eze1Department of Medical Laboratory Sciences, College of Health Sciences, Ebonyi State University, Abakaliki,

Nigeria.2Department of Microbiology, University of Maiduguri, Borno State, Nigeria.

ABSTRACT Streptococcus pneumoniae is one of the major bacteria colonises the nasopharyngeal cells of asymptomatically healthy individuals. The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as children less than 2 years, the elderly above 65 years, and the immunocompromised, the pneumococci may disseminate and cause life-bacteraemia/sepsis and meningitis. Report shows that approximately 1 million cof age die annually in developing countries from pneumococcal disease. The treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several studies shows that global prevalence of penicilvaries between 18.2% to 22.1% and 24.6% to 31.8% respectively. Current prevention strategies include the use of pneumococcal polysaccharide vaccines and conjugates vaccines. The capsular polysavaccines are antibody dependent and are poorly immunogenic in the target groups and also does not elicit immunologic memory. In contrast, the conjugate vaccines have shown high efficacy, but limited as they only provide protection against the capscapsular switch in types not incorporated in the conjugate vaccines. understanding of the structure and function of various pathogenicity and virulence factors have pway for the possibility of developing protein vaccines. This review focuses on pneumococcal virulence factors and the potential targets for KEY WORDS: Streptococcus pneumoniaeprotein-based pneumococcal vaccines, virulence factors. Received for Publication: 15/03/13Corresponding author:[email protected]

INTRODUCTION Streptococcus pneumoniae is colonises the nasopharyngeal cells and is carried asymptomatically by healthy individuals. The adherence and colonization of the nasopharyngeal cells is thought to be mediated by the interactions between choline binding protein A (CbpA) and human polymand this interaction also facilitates the invasion of nasopharyngeal epithelial cells (Rosenow addition, pneumococcal surface protein A (PspA) interacts with apolactoferrin interfering with the apolactoferrin-mediated killing of Streptococcus pneumoniaeet al., 2004). This interaction is shown in figure 1.2. The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as children less than 2 years, the elderly above 65 years, and the immunocompromised, the pneumococci may disseminate and cause lifebacteraemia/sepsis and meningitis (McCullers and Tuomanen, 2001; Iannelli Kim et al., 2012). Report shows that approximately 1 million children less than 5 yearsdeveloping countries from pneumococcal disease (Swiatto Treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several studies shows that global prevalence of penicillin

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27

Continental J. Medical Research 7 (1): 27 -45, 2013 ISSN: 2141 © Wilolud Journals, 2013 http://www.wiloludjournal.com

doi:10.5707/cjmedres.2013.7.1.

Streptococcus pneumoniae: VIRULENCE FACTORS AND THEIR ROLE IN PATHOGENESIS

Ukpai A. Eze1, Adam Mustapha2 and Amos Nworie1

Department of Medical Laboratory Sciences, College of Health Sciences, Ebonyi State University, Abakaliki, Department of Microbiology, University of Maiduguri, Borno State, Nigeria.

is one of the major bacteria cause of respiratory tract infections and colonises the nasopharyngeal cells of asymptomatically healthy individuals. The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as

an 2 years, the elderly above 65 years, and the immunocompromised, the pneumococci -threatening disease, including causing otitis media, pneumonia,

bacteraemia/sepsis and meningitis. Report shows that approximately 1 million children less than 5 years of age die annually in developing countries from pneumococcal disease. The treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several studies shows that global prevalence of penicillin-resistant and macrolide-resistant Streptococcus pneumoniaevaries between 18.2% to 22.1% and 24.6% to 31.8% respectively. Current prevention strategies include the use of pneumococcal polysaccharide vaccines and conjugates vaccines. The capsular polysavaccines are antibody dependent and are poorly immunogenic in the target groups and also does not elicit immunologic memory. In contrast, the conjugate vaccines have shown high efficacy, but limited as they only provide protection against the capsular serotypes/groups present in the vaccine resulting to capsular switch in types not incorporated in the conjugate vaccines. However, recent advances in the understanding of the structure and function of various pathogenicity and virulence factors have pway for the possibility of developing protein vaccines. This review focuses on pneumococcal virulence

and the potential targets for protein-based pneumococcal vaccine production.

Streptococcus pneumoniae, Capsular polysaccharide vaccines, conjugate vaccines, based pneumococcal vaccines, virulence factors.

3 Accepted for Publication: [email protected]

is colonises the nasopharyngeal cells and is carried asymptomatically by healthy individuals. The adherence and colonization of the nasopharyngeal cells is thought to be mediated by the interactions between choline binding protein A (CbpA) and human polymeric immunoglobin receptor (hpIgR) and this interaction also facilitates the invasion of nasopharyngeal epithelial cells (Rosenow addition, pneumococcal surface protein A (PspA) interacts with apolactoferrin interfering with the

Streptococcus pneumoniae in the nasopharynx and promotes carriage (Shaper ., 2004). This interaction is shown in figure 1.2.

The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as children less than 2 years, the elderly above 65 years, and the immunocompromised, the pneumococci may disseminate and cause life-threatening disease, including causing otitis media, pneumonia, bacteraemia/sepsis and meningitis (McCullers and Tuomanen, 2001; Iannelli et al., 2004; Tufari

., 2012). Report shows that approximately 1 million children less than 5 years of age die annually in developing countries from pneumococcal disease (Swiatto et al., 2003).

Treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several studies shows that global prevalence of penicillin-resistant and macrolide-resistant Streptococcus pneumoniae

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.2013.7.1.27.45

VIRULENCE FACTORS AND THEIR ROLE IN

Department of Medical Laboratory Sciences, College of Health Sciences, Ebonyi State University, Abakaliki, Department of Microbiology, University of Maiduguri, Borno State, Nigeria.

cause of respiratory tract infections and colonises the nasopharyngeal cells of asymptomatically healthy individuals. The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as

an 2 years, the elderly above 65 years, and the immunocompromised, the pneumococci threatening disease, including causing otitis media, pneumonia,

hildren less than 5 years of age die annually in developing countries from pneumococcal disease. The treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several studies

Streptococcus pneumoniae varies between 18.2% to 22.1% and 24.6% to 31.8% respectively. Current prevention strategies include the use of pneumococcal polysaccharide vaccines and conjugates vaccines. The capsular polysaccharide vaccines are antibody dependent and are poorly immunogenic in the target groups and also does not elicit immunologic memory. In contrast, the conjugate vaccines have shown high efficacy, but limited

ular serotypes/groups present in the vaccine resulting to However, recent advances in the

understanding of the structure and function of various pathogenicity and virulence factors have paved way for the possibility of developing protein vaccines. This review focuses on pneumococcal virulence

accines, conjugate vaccines,

Accepted for Publication: 07/05/13

is colonises the nasopharyngeal cells and is carried asymptomatically by healthy individuals. The adherence and colonization of the nasopharyngeal cells is thought to be mediated by the

eric immunoglobin receptor (hpIgR) and this interaction also facilitates the invasion of nasopharyngeal epithelial cells (Rosenow et al., 1997). In addition, pneumococcal surface protein A (PspA) interacts with apolactoferrin interfering with the

in the nasopharynx and promotes carriage (Shaper

The development of disease condition is often preceded by nasopharyngeal colonisation. In susceptible individuals such as children less than 2 years, the elderly above 65 years, and the immunocompromised, the

atening disease, including causing otitis media, pneumonia, ., 2004; Tufari et al., 2011;

of age die annually in

Treatment of pneumococcal infections has been complicated by rising trend of antibiotic resistance. Several Streptococcus pneumoniae


Ukpai A. Eze et al.,: varies between 18.2% to 22.1% and 24.6% to 31.8% respectively (Felmingham, 2002; Jacoobs most common serotypes resistant to penicillin and macrolides include 6A, 6B, 9V, 14, 19A, 19F and 23F (Whitney et al., 2000). Current prevention strategies include pneumococcal 23which covers the serotypes implicated in approximately 85% of disease in the US and Europe, 62.9% in Taiwan, 72.9% in Japan, 58% in Brazil and 79.9 % in India (Lee addition, a 7-valent, 9-valent, 10-valent and 13been introduced (Tafuri et al., 2011; Kim dependent and are poorly immunogenic in the target groups; young children, elderly people and immunocompromised individuals, and also does not elicit immunologic memory (Briles Vidyashankara et al., 2012). The conjugate vaccines have shown high efficacy, but limited as protection against the capsular serotypes/groups present in the vaccine resulting to capsular switch in types not incorporated in the conjugate vaccines (Kim Therefore, to overcome the increasing frequency of antibioticon the understanding of the mechanisms of pneumococcal virulence factors and development ofvaccines is needed. This review focuses on the various surface components implicated in nasopharyngeal colonisation and adherence, including PspA, CbpA/PspC, Pneumococcal adherencepneumolysin and neuraminidase, and the potential targets for Pneumococcal serotype distribution and clinicalAsymptomatic pneumococcal colonisation of the nasopharynx is an important factor for disease initiation and provides the niche from where the bacteria can progress to the alveolar space, blood stream, middle ear or brain and cause pneumonia, septicaemia, otitis media and meningitis, respectively (MeCullers and Tuomanen, 2001). Pneumococcal carriage is more common in children compared to adults, reaching a prevalence of 55% at the age of three years (Bogaert et al., 2004). Some underlying medical codisease, including congenital immunodeficiency, Human Immunodeficiency Virus (HIV), leukaemia, lymphoma, sickle cell disease and tissue transplantation (CDC, 1997). Other predisposing conditions to pneumococcal disease include viral respiratory disease, chronic bronchitis, chronic obstructive pulmonary disease and smoking. The various clinical disease of In a review, Bogaert et al., (2004) reported that serotypesfound in nasopharyngeal colonisation. However, Syrjanen and colleagues reported that serotypes 6A, 6B, 23F, 19F, 11 and 14 were common isolates from nasopharyngeal samples from Finland (Syrjanen Netherlands, the common serotypes include 19F, 6B, 6A, 9V, and 23F (Bogaert serotypes 6B, 19F, 23F, 14 and 18C are common among children less than 2 years of age in Greece (Syrogiannopoulos et al., 2000), whereas serotypes 2004). In contrast, Soewignjo et al., (2001) reported that serogroups 6, 23, 15, 33, 19, 12, and 3 were common in Indonesia one series. In Kenya, the predominant serotypes were 13, 15, 14, 2004). The reasons for the observed differences are unclear. It has been speculated that living condition with poverty, crowding and exposure to patients with active diseases may partly account for their dominance in developing countries. Acute otitis media (AOM) has been reported as the most common disease condition associated with Streptococcus pneumoniae and remains the major predisposing factor for the development of antimicrobial resistant pneumococci (Hausdorff et albiofilms in the middle ear enhancing recurrence infection as well as promoting horizontal gene transfer (McEllistrem et al., 2007). Hausdorff found in 13-25% of middle ear fluid of those with otitis interna, 14 and 6B were isolated in 6of the isolates were 6A, 19A, and 9V. They also reported that serotypes 1, 3 and 5 are the major causes of acute otitis media in children less than 6 months old. In contrast, O’ Brien and Santosham, (2004) showed that serotypes 4, 6B, 9V, 18C, 19F and 23F are the common causes of invasive and middle ear infections in United States. In their research, Kilpi et al., (2001) reported that serpredominant serotypes associated with acute otitis media in Finland. This is similar to earlier report indicating that serotypes 19, 6, 3, 23, 11 and 18 are the common cause of acute otitis media in Finland (Luot1981). However, in another series Showal et al., (2006) showed that serotypes 1, 3, 5, 18C, 19A and 19F are the


28

.,:Continental J. Medical Research 7 (1): 27 -45, 2013

varies between 18.2% to 22.1% and 24.6% to 31.8% respectively (Felmingham, 2002; Jacoobs et almost common serotypes resistant to penicillin and macrolides include 6A, 6B, 9V, 14, 19A, 19F and 23F

., 2000). Current prevention strategies include pneumococcal 23-valent polysaccharide vaccine cated in approximately 85% of disease in the US and Europe, 62.9% in Taiwan,

72.9% in Japan, 58% in Brazil and 79.9 % in India (Lee et al., 1991; Ferreira et al., 2006; Briles valent and 13-valent pneumococcal polysaccharide conjugate vaccines have

., 2011; Kim et al., 2012). The capsular polysaccharide vaccines are antibody unogenic in the target groups; young children, elderly people and

immunocompromised individuals, and also does not elicit immunologic memory (Briles ). The conjugate vaccines have shown high efficacy, but limited as they only provide

protection against the capsular serotypes/groups present in the vaccine resulting to capsular switch in types not incorporated in the conjugate vaccines (Kim et al., 2012).

Therefore, to overcome the increasing frequency of antibiotic-resistant strains and capsular switch, emphasises on the understanding of the mechanisms of pneumococcal virulence factors and development of

is needed. This review focuses on the various surface components implicated in nasopharyngeal isation and adherence, including PspA, CbpA/PspC, Pneumococcal adherence-virulence factor A (PavA),

pneumolysin and neuraminidase, and the potential targets for protein-based pneumococcal vaccine production.

Pneumococcal serotype distribution and clinical disease Asymptomatic pneumococcal colonisation of the nasopharynx is an important factor for disease initiation and provides the niche from where the bacteria can progress to the alveolar space, blood stream, middle ear or brain

caemia, otitis media and meningitis, respectively (MeCullers and Tuomanen, 2001). Pneumococcal carriage is more common in children compared to adults, reaching a prevalence of 55% at the

., 2004). Some underlying medical conditions are associated with pneumococcal disease, including congenital immunodeficiency, Human Immunodeficiency Virus (HIV), leukaemia, lymphoma, sickle cell disease and tissue transplantation (CDC, 1997). Other predisposing conditions to

ease include viral respiratory disease, chronic bronchitis, chronic obstructive pulmonary disease and smoking. The various clinical disease of Streptococcus pneumoniae is presented in figure 1.1.

., (2004) reported that serotypes 6A, 6B, 14, 15, 18C, 19F, and 23F are frequently found in nasopharyngeal colonisation. However, Syrjanen and colleagues reported that serotypes 6A, 6B, 23F, 19F, 11 and 14 were common isolates from nasopharyngeal samples from Finland (Syrjanen Netherlands, the common serotypes include 19F, 6B, 6A, 9V, and 23F (Bogaert et al., 2004). Similarly, serotypes 6B, 19F, 23F, 14 and 18C are common among children less than 2 years of age in Greece

., 2000), whereas serotypes 6B, 14, 19F, and 23 are common in USA (Bogaert ., (2001) reported that serogroups 6, 23, 15, 33, 19, 12, and 3 were common

in Indonesia one series. In Kenya, the predominant serotypes were 13, 15, 14, 6b, and 19F (Bogaert The reasons for the observed differences are unclear. It has been speculated that living condition with

poverty, crowding and exposure to patients with active diseases may partly account for their dominance in

Acute otitis media (AOM) has been reported as the most common disease condition associated with and remains the major predisposing factor for the development of antimicrobial

et al., 2002). This may be attributed to the continuous development of biofilms in the middle ear enhancing recurrence infection as well as promoting horizontal gene transfer

., 2007). Hausdorff et al., (2002) in a global study showed that serotypes 19F and 25% of middle ear fluid of those with otitis interna, 14 and 6B were isolated in 6-18% while 5

of the isolates were 6A, 19A, and 9V. They also reported that serotypes 1, 3 and 5 are the major causes of acute en less than 6 months old. In contrast, O’ Brien and Santosham, (2004) showed that

serotypes 4, 6B, 9V, 18C, 19F and 23F are the common causes of invasive and middle ear infections in United ., (2001) reported that serotypes 19F, 23F, 6A, 6B, 14 and 11 were the

predominant serotypes associated with acute otitis media in Finland. This is similar to earlier report indicating that serotypes 19, 6, 3, 23, 11 and 18 are the common cause of acute otitis media in Finland (Luot1981). However, in another series Showal et al., (2006) showed that serotypes 1, 3, 5, 18C, 19A and 19F are the


et al., 2003). The most common serotypes resistant to penicillin and macrolides include 6A, 6B, 9V, 14, 19A, 19F and 23F

valent polysaccharide vaccine cated in approximately 85% of disease in the US and Europe, 62.9% in Taiwan,

., 2006; Briles et al., 1998). In valent pneumococcal polysaccharide conjugate vaccines have ., 2012). The capsular polysaccharide vaccines are antibody

unogenic in the target groups; young children, elderly people and immunocompromised individuals, and also does not elicit immunologic memory (Briles et al., 1998;

they only provide protection against the capsular serotypes/groups present in the vaccine resulting to capsular switch in types not

sistant strains and capsular switch, emphasises on the understanding of the mechanisms of pneumococcal virulence factors and development of protein

is needed. This review focuses on the various surface components implicated in nasopharyngeal virulence factor A (PavA),

based pneumococcal vaccine production.

Asymptomatic pneumococcal colonisation of the nasopharynx is an important factor for disease initiation and provides the niche from where the bacteria can progress to the alveolar space, blood stream, middle ear or brain

caemia, otitis media and meningitis, respectively (MeCullers and Tuomanen, 2001). Pneumococcal carriage is more common in children compared to adults, reaching a prevalence of 55% at the

nditions are associated with pneumococcal disease, including congenital immunodeficiency, Human Immunodeficiency Virus (HIV), leukaemia, lymphoma, sickle cell disease and tissue transplantation (CDC, 1997). Other predisposing conditions to

ease include viral respiratory disease, chronic bronchitis, chronic obstructive pulmonary is presented in figure 1.1.

6A, 6B, 14, 15, 18C, 19F, and 23F are frequently found in nasopharyngeal colonisation. However, Syrjanen and colleagues reported that serotypes 6A, 6B, 23F, 19F, 11 and 14 were common isolates from nasopharyngeal samples from Finland (Syrjanen et al., 2001). In

., 2004). Similarly, serotypes 6B, 19F, 23F, 14 and 18C are common among children less than 2 years of age in Greece

6B, 14, 19F, and 23 are common in USA (Bogaert et al., ., (2001) reported that serogroups 6, 23, 15, 33, 19, 12, and 3 were common

(Bogaert et al., The reasons for the observed differences are unclear. It has been speculated that living condition with

poverty, crowding and exposure to patients with active diseases may partly account for their dominance in

Acute otitis media (AOM) has been reported as the most common disease condition associated with and remains the major predisposing factor for the development of antimicrobial

ay be attributed to the continuous development of biofilms in the middle ear enhancing recurrence infection as well as promoting horizontal gene transfer

., (2002) in a global study showed that serotypes 19F and 23F were 18% while 5-10%

of the isolates were 6A, 19A, and 9V. They also reported that serotypes 1, 3 and 5 are the major causes of acute en less than 6 months old. In contrast, O’ Brien and Santosham, (2004) showed that

serotypes 4, 6B, 9V, 18C, 19F and 23F are the common causes of invasive and middle ear infections in United otypes 19F, 23F, 6A, 6B, 14 and 11 were the

predominant serotypes associated with acute otitis media in Finland. This is similar to earlier report indicating that serotypes 19, 6, 3, 23, 11 and 18 are the common cause of acute otitis media in Finland (Luotonen et al., 1981). However, in another series Showal et al., (2006) showed that serotypes 1, 3, 5, 18C, 19A and 19F are the


Ukpai A. Eze et al.,: most frequent serotypes associated to acute otitis mediatypeable pneumococci are not involved in the development of acute otitis media. Recombination exchanges at the capsular biosynthetic locus results in serotype and this have been shown among pneumococ(Coffey et al., 1998). In Israel, the most common serotypes associated with acute otitis media were 14, 19F, 23F, 19A, 6B, 6B, 11A, 33 A and 18C (Moschoioni infections are generally related to age, predisposing factors, the immune status of the host, and other virulence factors of the infecting pneumococcal strain and that the infecting serotype/type is of minor importance. Bacteraemia, pneumonia and meningitis, including other systemic diseases such as endocarditis and pleural empyema are termed invasive pneumococcal disease. According to Hausdorff 2, 5, 6, 14, 19, and 23 are the most pred9V, 3, 23F and 7F are highly associated with invasive pneumococcal disease (Kanasanterveyslaitos However, O’Brien and Santosham, (2004) demonstrated that serotypes 4, 6mostly associated with invasive pneumococcal disease in USA. In another series, Brueggemann et al., (2003) reported that serotypes 1, 4, 14, and 18C are the major pneumococcal types involved in invasive disease in England, whereas serotypes 14, 9, 6, 19, 23, 8 and 4 causes invasive disease in Scotland (Kyaw et al., 2003). In contrast, the most common serogroups associated with invasive disease in Bangladesh are 2, 1, 14, 5, 45, and 12A (Saha et al., 2009). In addition, invaand 18C in Sweden (Sandgren et al., 2004). Furthermore, in India pneumococcal serotypes 1, 6, 19, 7, 5, 15, 14, 4, 16, and 18 cause invasive disease (INCLEAN, 1999). In the HIV positive padisease is caused by serotypes 6A, 6B, 9N, 9V, 18C, 19A, 19F, and 23F (Fry et al., 2003). The variations in the serotype distribution in invasive pneumococcal disease may be attributed to the introduction of the current 23valent vaccine which includes the serotypes that cause 88% of invasive disease in USA and 96% of those in the UK. Pneumococcal virulence factors and potential targets for proteinStreptococcus pneumoniae possesses several virulent factors thatnasopharynx and development of invasive disease. Currently, there are 91 know capsular serotypes of Streptococcus pneumoniae with variations in the polysaccharide structure occurring between different capsular serotypes (Park et al., 2007). The representation of the cell membrane, cell wall and capsule of pneumoniae is shown in figure 1. 3. PiaA PiaA is one of the various iron acquisition systems in immunogenic, found in all pneumococcal serotypes and highly conserved between strains, and this makes it a potencial vaccine candidate (Jomaa et althe nasopharyngeal washing of a mice mmight be responsible for adherence and colonisation. Intranasal and intraperitoneal immunisation has been effective in protecting against systemic infection and pneumonia respectively (Brown e2006).


29


most frequent serotypes associated to acute otitis media in Israel. They further stated that 6A, 6B, 15A and nontypeable pneumococci are not involved in the development of acute otitis media. Recombination exchanges at the capsular biosynthetic locus results in serotype and this have been shown among pneumococ

., 1998). In Israel, the most common serotypes associated with acute otitis media were 14, 19F, 23F, 19A, 6B, 6B, 11A, 33 A and 18C (Moschoioni et al., 2010).It can be deduced that the outcome of clinical

related to age, predisposing factors, the immune status of the host, and other virulence factors of the infecting pneumococcal strain and that the infecting serotype/type is of minor importance.

Bacteraemia, pneumonia and meningitis, including other systemic diseases such as endocarditis and pleural empyema are termed invasive pneumococcal disease. According to Hausdorff et al., (2005), serotypes/groups 1, 2, 5, 6, 14, 19, and 23 are the most predominant types in invasive disease globally. In Finland, serotypes 14, 4, 9V, 3, 23F and 7F are highly associated with invasive pneumococcal disease (Kanasanterveyslaitos However, O’Brien and Santosham, (2004) demonstrated that serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F were mostly associated with invasive pneumococcal disease in USA. In another series, Brueggemann et al., (2003) reported that serotypes 1, 4, 14, and 18C are the major pneumococcal types involved in invasive disease in

whereas serotypes 14, 9, 6, 19, 23, 8 and 4 causes invasive disease in Scotland (Kyaw et al., 2003). In contrast, the most common serogroups associated with invasive disease in Bangladesh are 2, 1, 14, 5, 45, and

., 2009). In addition, invasive pneumococcal disease is caused by serotypes 1, 4, 7F, 9V, 12F, ., 2004). Furthermore, in India pneumococcal serotypes 1, 6, 19, 7, 5, 15, 14,

4, 16, and 18 cause invasive disease (INCLEAN, 1999). In the HIV positive patients, invasive pneumococcal disease is caused by serotypes 6A, 6B, 9N, 9V, 18C, 19A, 19F, and 23F (Fry et al., 2003). The variations in the serotype distribution in invasive pneumococcal disease may be attributed to the introduction of the current 23

ent vaccine which includes the serotypes that cause 88% of invasive disease in USA and 96% of those in the

Pneumococcal virulence factors and potential targets for protein-based vaccines possesses several virulent factors that promote their establishment in the

nasopharynx and development of invasive disease. Currently, there are 91 know capsular serotypes of with variations in the polysaccharide structure occurring between different capsular

., 2007). The representation of the cell membrane, cell wall and capsule of

PiaA is one of the various iron acquisition systems in S. pneumoniae. RFLP analysis indicates that it is highly mmunogenic, found in all pneumococcal serotypes and highly conserved between strains, and this makes it a

et al., 2006). LeMessurier et al., (2006) demonstrated high level of PiaA in the nasopharyngeal washing of a mice model challenged with D39 and WCH16 strains and proposed that it might be responsible for adherence and colonisation. Intranasal and intraperitoneal immunisation has been effective in protecting against systemic infection and pneumonia respectively (Brown et al., 2001; Jomaa


in Israel. They further stated that 6A, 6B, 15A and non-typeable pneumococci are not involved in the development of acute otitis media. Recombination exchanges at the capsular biosynthetic locus results in serotype and this have been shown among pneumococcal isolates

., 1998). In Israel, the most common serotypes associated with acute otitis media were 14, 19F, ., 2010).It can be deduced that the outcome of clinical

related to age, predisposing factors, the immune status of the host, and other virulence factors of the infecting pneumococcal strain and that the infecting serotype/type is of minor importance.

Bacteraemia, pneumonia and meningitis, including other systemic diseases such as endocarditis and pleural ., (2005), serotypes/groups 1,

ominant types in invasive disease globally. In Finland, serotypes 14, 4, 9V, 3, 23F and 7F are highly associated with invasive pneumococcal disease (Kanasanterveyslaitos et al., 2005).

B, 9V, 14, 18C, 19F, and 23F were mostly associated with invasive pneumococcal disease in USA. In another series, Brueggemann et al., (2003) reported that serotypes 1, 4, 14, and 18C are the major pneumococcal types involved in invasive disease in

whereas serotypes 14, 9, 6, 19, 23, 8 and 4 causes invasive disease in Scotland (Kyaw et al., 2003). In contrast, the most common serogroups associated with invasive disease in Bangladesh are 2, 1, 14, 5, 45, and

sive pneumococcal disease is caused by serotypes 1, 4, 7F, 9V, 12F, ., 2004). Furthermore, in India pneumococcal serotypes 1, 6, 19, 7, 5, 15, 14,

tients, invasive pneumococcal disease is caused by serotypes 6A, 6B, 9N, 9V, 18C, 19A, 19F, and 23F (Fry et al., 2003). The variations in the serotype distribution in invasive pneumococcal disease may be attributed to the introduction of the current 23-

ent vaccine which includes the serotypes that cause 88% of invasive disease in USA and 96% of those in the

promote their establishment in the nasopharynx and development of invasive disease. Currently, there are 91 know capsular serotypes of

with variations in the polysaccharide structure occurring between different capsular ., 2007). The representation of the cell membrane, cell wall and capsule of Streptococcus

. RFLP analysis indicates that it is highly mmunogenic, found in all pneumococcal serotypes and highly conserved between strains, and this makes it a

., (2006) demonstrated high level of PiaA in odel challenged with D39 and WCH16 strains and proposed that it

might be responsible for adherence and colonisation. Intranasal and intraperitoneal immunisation has been t al., 2001; Jomaa et al.,


Ukpai A. Eze et al.,:

Figure 1.1: Infections caused by S. pneumoniaepneumococcal diseases are preceded by nasopharyngeal carriage, after which the bacterium can spread to the middle ear causing otitis media or disseminate to the lungs causing pneumonia. During infecbacteria may penetrate into the blood circulation, from which they can spread through the whole body. Otitis media might also cause infection of the meninges. Some wellcontributions to virulence at that particular site in the human or murine body, are indicated in dotted boxes. Ami- AliA/B, oligopeptide ABC transporter; CbpA, choline binssding protein A; CiaRH, the Cia twocomponent system; ComDE, two-component system specific for sensing of competeCps, polysaccharide capsule; Iga, immunoglobulin A1 protease; LytA, autolysin A; LytB, autolysin B; NanA, neuraminidase A; NanB, neuraminidase B; PavA, pneumococcal adherence and virulence factor A; phosphocholine; PcpA, choline binding protein PcpA; Ply, pneumolysin; PsaA, pneumococcal surface adhesin A [Mn2+ uptake ABC transporter]; PspA, pneumococcal surface protein A; ZmpC, metalloprotease.Source: Modified from Hendriksen et al Neuraminidase Neuraminidase (nanA), an exoglycosidase that cleaves the terminal sialic acid moieties from glycolipids, mucins, glycoproteins and oligopolysaccharides, is found in virtually all respiratory pathogens. The nanA and nanB are the major neuraminidase found in gene is universally present in all pneumococcal strains (Pettigrew 96% of a series of isolates and nanC gene Whenviewed on transparent media, pneumococcal colonies can be transparent or opaque. The transparent phenotype is frequently linked to nasopharyngeal colonization and invasion of the brain microvascular endothelial cells whereas the opaque phenotype is common in the blood during sepsis in a mice model (LeMessurier et al., 2006). King et alisolated from nasopharynx using a microarray technique. There are evidences showing thdesialation of the cell surfaces of Neisseria meningitidisglycoconjugate receptors, including lactoferrin and IgA2 (King nasopharyngeal carriage of other bacterial species, thereby enhancing the adhesion of respiratory epithelia. However, NanA is not associated with sepsis because nanA knockout mutant was not attenuated after an intraperitoneal inoculation in a murine model ( Choline Binding Proteins Streptococcus pneumoniae has several surface proteins called choline binding proteins (CBPs) that are attached to the cell wall techoic and lipotechoic acids (Rosenow same portion of choline Binding Region (CBR) consisting of between 2 and 10 highly conserved 20 amino acid repeats which bind non-covalently to chop residues (Garcia be widely described include autolysin (LytA) and pneumococcal surface protein A, PspA (Talkington 1991; Yother and Briles, 1992). Subsequently, other CBPs such as CbpA or PspC (Rosenow Brooks-Walter et al., 1999), cell wall hydrolases (LytB and LytC), amidase (CbpD), and serine protease (CbpG)


30


S. pneumoniae. Black arrows indicate the progression of infection. All

pneumococcal diseases are preceded by nasopharyngeal carriage, after which the bacterium can spread to the middle ear causing otitis media or disseminate to the lungs causing pneumonia. During infection of the lungs, bacteria may penetrate into the blood circulation, from which they can spread through the whole body. Otitis media might also cause infection of the meninges. Some well-known examples of proteins, which have

that particular site in the human or murine body, are indicated in dotted boxes. AliA/B, oligopeptide ABC transporter; CbpA, choline binssding protein A; CiaRH, the Cia two

component system specific for sensing of competence stimulating peptide; Cps, polysaccharide capsule; Iga, immunoglobulin A1 protease; LytA, autolysin A; LytB, autolysin B; NanA, neuraminidase A; NanB, neuraminidase B; PavA, pneumococcal adherence and virulence factor A;

ine binding protein PcpA; Ply, pneumolysin; PsaA, pneumococcal surface adhesin A [Mn2+ uptake ABC transporter]; PspA, pneumococcal surface protein A; ZmpC, metalloprotease.

et al., (2009).

), an exoglycosidase that cleaves the terminal sialic acid moieties from glycolipids, mucins, glycoproteins and oligopolysaccharides, is found in virtually all respiratory pathogens. The nanA and nanB are the major neuraminidase found in S. pneumoniae, although nanC can also be present. However,

is universally present in all pneumococcal strains (Pettigrew et al., 2006) whereas nanB genegene was present in only 51% of the same series (Pettigrew

viewed on transparent media, pneumococcal colonies can be transparent or opaque. The transparent phenotype is frequently linked to nasopharyngeal colonization and invasion of the brain microvascular

ue phenotype is common in the blood during sepsis in a mice model et al., (2004) demonstrated that nanA was more abundant in pneumococci

isolated from nasopharynx using a microarray technique. There are evidences showing that nanA can cause Neisseria meningitidis and Haemophilus influenzae and also modify the

glycoconjugate receptors, including lactoferrin and IgA2 (King et al., 2004). This is thought to decrease the e of other bacterial species, thereby enhancing the adhesion of S. pneumoniae

respiratory epithelia. However, NanA is not associated with sepsis because nanA knockout mutant was not attenuated after an intraperitoneal inoculation in a murine model (Berry and Paton, 2000).

has several surface proteins called choline binding proteins (CBPs) that are attached to the cell wall techoic and lipotechoic acids (Rosenow et al., 1997; Garcia et al., 1998). CPB is found at the same portion of choline Binding Region (CBR) consisting of between 2 and 10 highly conserved 20 amino acid

covalently to chop residues (Garcia et al., 1998). The first two pneumococcal CBPs to described include autolysin (LytA) and pneumococcal surface protein A, PspA (Talkington

1991; Yother and Briles, 1992). Subsequently, other CBPs such as CbpA or PspC (Rosenow ), cell wall hydrolases (LytB and LytC), amidase (CbpD), and serine protease (CbpG)


. Black arrows indicate the progression of infection. All pneumococcal diseases are preceded by nasopharyngeal carriage, after which the bacterium can spread to the

tion of the lungs, bacteria may penetrate into the blood circulation, from which they can spread through the whole body. Otitis

known examples of proteins, which have that particular site in the human or murine body, are indicated in dotted boxes.

AliA/B, oligopeptide ABC transporter; CbpA, choline binssding protein A; CiaRH, the Cia two-nce stimulating peptide;

Cps, polysaccharide capsule; Iga, immunoglobulin A1 protease; LytA, autolysin A; LytB, autolysin B; NanA, neuraminidase A; NanB, neuraminidase B; PavA, pneumococcal adherence and virulence factor A; PCho,

ine binding protein PcpA; Ply, pneumolysin; PsaA, pneumococcal surface adhesin A [Mn2+ uptake ABC transporter]; PspA, pneumococcal surface protein A; ZmpC, metalloprotease.

), an exoglycosidase that cleaves the terminal sialic acid moieties from glycolipids, mucins, glycoproteins and oligopolysaccharides, is found in virtually all respiratory pathogens. The nanA and

, although nanC can also be present. However, nanA genewas present in

rew et al., 2006). viewed on transparent media, pneumococcal colonies can be transparent or opaque. The transparent

phenotype is frequently linked to nasopharyngeal colonization and invasion of the brain microvascular ue phenotype is common in the blood during sepsis in a mice model

., (2004) demonstrated that nanA was more abundant in pneumococci at nanA can cause

and also modify the ., 2004). This is thought to decrease the

S. pneumoniae to the respiratory epithelia. However, NanA is not associated with sepsis because nanA knockout mutant was not

has several surface proteins called choline binding proteins (CBPs) that are attached ., 1998). CPB is found at the

same portion of choline Binding Region (CBR) consisting of between 2 and 10 highly conserved 20 amino acid ., 1998). The first two pneumococcal CBPs to

described include autolysin (LytA) and pneumococcal surface protein A, PspA (Talkington et al., 1991; Yother and Briles, 1992). Subsequently, other CBPs such as CbpA or PspC (Rosenow et al., 1997;

), cell wall hydrolases (LytB and LytC), amidase (CbpD), and serine protease (CbpG)


Ukpai A. Eze et al.,: were demonstrated (Garcia et al., 1999; Gosink least 10 pneumococcal CBPs have been characterized (Kausmally, 2005). Pneumococcal Surface Protein A (PspAproteins associated with virulence. PspA was the first surface exposed protein that was discovered to bind choline residues (Hollinghead et al., 2000). PspA is attached to the cell wall throughphosphorylcholine (ChoP) moieties on techoic and lipotechoic acids and its Csequence homology with CBR of CbpA (Brooksextends beyond the polysaccharide capsule (Yother and Briles, 1992). The molecular weight of PspA varies between strains from 67-99 kDa and is found in all clinically important serotypes of 1990; Waltman et al., 1990; Jedrzejas pneumoniae during infection and influence complement deposition through alternative pathway, but it is still unclear how this happens (Ogunniyi et althe α-helical N-terminal region of PspA is immunogenic and further showed that immunisation with a 43 kDa fragment containing this portion protects a mice challenged by intravenous and intratracheal inoculation. In human clinical studies, prior presence of antibodies to PspA was shown to influence the susceptibility of pneumoniae infection (Talkington et alpneumococcal vaccine (Briles et al., 1996; Briles There is increasing evidence showing that PspA have a role in inhibiting complementand colleagues reported that PspA-negative strains are cleared rapidly from blood after intravenous inoculation, but levels of isogenic PspA-positive strain increased rapidly (Tu deficient in C3 or factor B are unable clear mutant strains lacking PspA while C5 deficient mice cleared the same mutant strains. In addition, Serum C3 was significantly reduced within strain whereas no significant reduction of serum C3 occurred in mice infected with a PspAal., 1999). Similarly, a profound increase in C3 binding was discovered when both both PspApneumococci were incubated with anticollegues demonstrated that mutant pneumococcal strains without PspA and pneumolysin were unable to spread from the lung into the blood in mice with normal complethat C3 deposition is inhibited by PspA modulating the alternative pathway and pneumolysin inhibition of the classical pathway, which helps in the establishment of demonstrated that PspA is found majorly in blood in both D39 and WCH16 strains using RNA microarray, and proposed that PspA is a major virulent factor for sepsis than nasopharyngeal carriage. The inhibition of complement clearance of pneumococci by PspA in the blood enhances its ability to cause sepsis. Since highly immunogenic, it is possible that it can be used the development of a protein based vaccine. CbpA, also called PspC (Pneumococcal Surface Protein C) and SpsA protein IgA) is exposed to the surface of the pneumococcal capsule and is encoded by a heterogeneous group of mosaic genes (Brooks-Walter et al., 1999). In 1997, Rosenow and colleagues demonstrated that there is a reduction in the ability of CbpA-negative epithelial cells and endothelial cells when compared to the parent strain, and an almost 100nasopharyngeal carriage in an infant rat model indica(Rosenow et al., 1997). Similarly, Balachandran CbpA were unable to colonise the nasopharynx of a mouse model, and were unable to invade and multiply in the lungs. In addition, using RNA microarray LeMessurier and colleagues demonstrated that CbpA is the major virulent factor for the development of pneumonia in both D39 and WCH16 strains as more concentrations were detected in the lung of an animal model (LeMessurier promote pneumococcal adherence to the brain microvascular endothelsubarachnoid space (Ring et al., 1998; Orihuela Zhang et al., (2000) reported that lack of CbpA decreased the ability of mutant pneumococcal strain to invade the nasopharyngeal cells by more than 90% whenthat a knockout mice lacking pIgR trafficking has a delayed onset of bacteraemia after intranasal inoculation. As a result, they proposed that pneumococcal CbpA interact with human pIgR and invthe pIgR. This is similar to the report of Koedel


31


., 1999; Gosink et al., 2000; Kausmally et al., 2005). Reports inleast 10 pneumococcal CBPs have been characterized (Kausmally, 2005).

PspA)and Choline binding protein A (CbpA) are major choline binding proteins associated with virulence. PspA was the first surface exposed protein that was discovered to bind

., 2000). PspA is attached to the cell wall through the interface between phosphorylcholine (ChoP) moieties on techoic and lipotechoic acids and its C-terminal CBR, which has 95sequence homology with CBR of CbpA (Brooks-Walter et al., 1999). The highly charged N-

saccharide capsule (Yother and Briles, 1992). The molecular weight of PspA varies 99 kDa and is found in all clinically important serotypes of S. pneumoniae

1990; Waltman et al., 1990; Jedrzejas et al., 2000). Reports have indicated that PspA is upduring infection and influence complement deposition through alternative pathway, but it is still

et al., 2002; Yutse et al., 2005). Talkington et al., (1991) demterminal region of PspA is immunogenic and further showed that immunisation with a 43 kDa

fragment containing this portion protects a mice challenged by intravenous and intratracheal inoculation. In ior presence of antibodies to PspA was shown to influence the susceptibility of

et al., 1996; McCool et al., 2002). PspA is a potential candidate for ., 1996; Briles et al., 1998).

e is increasing evidence showing that PspA have a role in inhibiting complement-mediated opsonisation. Tu negative strains are cleared rapidly from blood after intravenous inoculation,

strain increased rapidly (Tu et al., 1999). They also showed that mice deficient in C3 or factor B are unable clear mutant strains lacking PspA while C5 deficient mice cleared the same mutant strains. In addition, Serum C3 was significantly reduced within 30 minutes with PspAstrain whereas no significant reduction of serum C3 occurred in mice infected with a PspA-positive strain (Tu

., 1999). Similarly, a profound increase in C3 binding was discovered when both both PspAci were incubated with anti-PspA (Ren et al., 2003; Ren et al., 2004). Furthermore, Yutse and

collegues demonstrated that mutant pneumococcal strains without PspA and pneumolysin were unable to spread from the lung into the blood in mice with normal complement function (Yutse et al., 2005). They also proposed that C3 deposition is inhibited by PspA modulating the alternative pathway and pneumolysin inhibition of the classical pathway, which helps in the establishment of S. pneumoniae septicaemia. LeMessuriedemonstrated that PspA is found majorly in blood in both D39 and WCH16 strains using RNA microarray, and proposed that PspA is a major virulent factor for sepsis than nasopharyngeal carriage. The inhibition of

ococci by PspA in the blood enhances its ability to cause sepsis. Since immunogenic, it is possible that it can be used the development of a protein based vaccine.

CbpA, also called PspC (Pneumococcal Surface Protein C) and SpsA (Streptococcus pneumoniaeprotein IgA) is exposed to the surface of the pneumococcal capsule and is encoded by a heterogeneous group of

., 1999). In 1997, Rosenow and colleagues demonstrated that there is a negative S. pneumoniae mutant (CbpA-) to bind cytokine-activated human lung

epithelial cells and endothelial cells when compared to the parent strain, and an almost 100-fold decrease in nasopharyngeal carriage in an infant rat model indicating that CbpA plays a role as adhesin in

., 1997). Similarly, Balachandran et al., (2002) reported that S. pneumoniae CbpA were unable to colonise the nasopharynx of a mouse model, and were unable to invade and multiply in the lungs. In addition, using RNA microarray LeMessurier and colleagues demonstrated that CbpA is the major

velopment of pneumonia in both D39 and WCH16 strains as more concentrations were detected in the lung of an animal model (LeMessurier et al., 2006). Furthermore, CbpA has also been shown to promote pneumococcal adherence to the brain microvascular endothelium and subsequent invasion of the

., 1998; Orihuela et al., 2004).

., (2000) reported that lack of CbpA decreased the ability of mutant pneumococcal strain to invade the nasopharyngeal cells by more than 90% when compared to the parent strain. Furthermore, they demonstrated that a knockout mice lacking pIgR trafficking has a delayed onset of bacteraemia after intranasal inoculation. As a result, they proposed that pneumococcal CbpA interact with human pIgR and invades cells by subversion of the pIgR. This is similar to the report of Koedel et al., (2002) which shows that CbpA is necessary for


., 2005). Reports indicate that at

and Choline binding protein A (CbpA) are major choline binding proteins associated with virulence. PspA was the first surface exposed protein that was discovered to bind

the interface between terminal CBR, which has 95-95%

-terminal region saccharide capsule (Yother and Briles, 1992). The molecular weight of PspA varies

S. pneumoniae (Crain et al., have indicated that PspA is up-regulated in S.

during infection and influence complement deposition through alternative pathway, but it is still ., (1991) demonstrated that

terminal region of PspA is immunogenic and further showed that immunisation with a 43 kDa fragment containing this portion protects a mice challenged by intravenous and intratracheal inoculation. In

ior presence of antibodies to PspA was shown to influence the susceptibility of S. ., 2002). PspA is a potential candidate for

mediated opsonisation. Tu negative strains are cleared rapidly from blood after intravenous inoculation,

., 1999). They also showed that mice deficient in C3 or factor B are unable clear mutant strains lacking PspA while C5 deficient mice cleared the

30 minutes with PspA-negative positive strain (Tu et

., 1999). Similarly, a profound increase in C3 binding was discovered when both both PspA- mutant and ., 2004). Furthermore, Yutse and

collegues demonstrated that mutant pneumococcal strains without PspA and pneumolysin were unable to spread ., 2005). They also proposed

that C3 deposition is inhibited by PspA modulating the alternative pathway and pneumolysin inhibition of the septicaemia. LeMessurier et al., (2006)

demonstrated that PspA is found majorly in blood in both D39 and WCH16 strains using RNA microarray, and proposed that PspA is a major virulent factor for sepsis than nasopharyngeal carriage. The inhibition of

ococci by PspA in the blood enhances its ability to cause sepsis. Since PspA is immunogenic, it is possible that it can be used the development of a protein based vaccine.

ccus pneumoniae secretary protein IgA) is exposed to the surface of the pneumococcal capsule and is encoded by a heterogeneous group of

., 1999). In 1997, Rosenow and colleagues demonstrated that there is a activated human lung

fold decrease in ting that CbpA plays a role as adhesin in S. pneumoniae

mutants lacking CbpA were unable to colonise the nasopharynx of a mouse model, and were unable to invade and multiply in the lungs. In addition, using RNA microarray LeMessurier and colleagues demonstrated that CbpA is the major

velopment of pneumonia in both D39 and WCH16 strains as more concentrations were ., 2006). Furthermore, CbpA has also been shown to

ium and subsequent invasion of the

., (2000) reported that lack of CbpA decreased the ability of mutant pneumococcal strain to invade compared to the parent strain. Furthermore, they demonstrated

that a knockout mice lacking pIgR trafficking has a delayed onset of bacteraemia after intranasal inoculation. As ades cells by subversion of

., (2002) which shows that CbpA is necessary for S.


Ukpai A. Eze et al.,: pneumoniae to invade blood-brain barrier by biand crossing the capillary endothelium by transcytosis. However, Brock pIgR-mediated invasion is only found in Detroitmediated pneumococcal invasion is strain and cell specific. CbpA is highly polymorphic (Iannelli and there is substantial strain to strain variation in 2006). In addition to a virulence role in adherence and invasion, CbpA is also involved in complement by binding to factor H (Dave the attachment of factor B to complement component 3b (C3b) and therefore, prevents host cells from being attacked by its own complement pathway (Dave binding pneumococcal CbpA, factor H is then able to bind C3b deposited on the the complement pathway at this crucial phase. In addition, CbpA could decrease alternative pathway activity by modulating the rate of C3 degradation to iC3b, causing dissociation of factor B (Bf) from the C3 convertase reducing C3b deposition, or inhibiting C3bBb formation by preferentially binding C3b. CbpA is a potential vaccine candidate as a result of its role in carriage and pathogenesis. Furthermore, the CbpA is extends beyond the capsule and therefore, carriage can beantibodies. Reports of immunization studies indicate that CbpA can be highly protective against in mice model following intra-peritoneal challenge (Brooks Pneumolysin The toxigenic potential of pneumolysin (Ply) in the pathogenesis of pneumococcal disease has been demonstrated and it is found in practically all clinical isolates of toxigenic potential lies on its interaction of the cell membranes which results in transmembrane pore formation allowing the influx of water, ions and some organic macromolecules, culminating to cell lysis (Boulnois 1991). In addition, it has been proposed that Ply may also induce upregulation of nitric oxide production by macrophages causing damage to the host’s cells (Braun been shown to cause activation of the classical pathwayantibody through binding of C1 to Ply domain which is common to the Fc portion of IgG (Paton Mitchell et al., 1991). Jounblat et al., (2003) demonstrated that the growth of blood is as a result of complement activating property of Ply. Various studies have shown the association of Ply and pneumococcal septicaemia, and reduction in replication and survival in the blood of an animal model was found in Ply-negative mutant strains (Benton The alteration of the plasma membrane integrity by ply has been shown to stimulate the production and release of cytokine IL-8 and TNFα by neutrophils (Cockeran mediated the production of TNFα, IL-deduced that the induction of inflammatory responses might be a contributing factor to the severity opneumococcal disease and the high mortality rate. Furthermore, Ply has been demonstrated to inhibit the beating of the cilia lining the respiratory epithelium increasing the accumulation of the bacteria in the lung which may result to pneumonia (Boulnois et alpathogenesis, and further research is needed to unlock these other roles. Zinc Metalloproteinases The pneumococcus produces large proteases on its surface which are mainly zincmetalloproteinases and previously sequenced genomes showed that four can be found in an isolate (Chiavolini al., 2003). These are frequently associated with invasive infections and virulence in serotype 4 pneumococci, but not associated with virulence in seserotype 19F (Chiavolini et al., 2003). The IgA1 protease and ZmpC are the only zinc metalloproteinases that are sufficiently characterized. The Immunoglobulin A1 protease allow the pneumocoexplains its substantial diversity as it is required to cleave structurally diverse substrates (Poulsen To cleave structurally diverse substrates, pneumococcal strains show variation in the num


32


brain barrier by binding to the human polymeric immunoglobin receptor (pIgR) and crossing the capillary endothelium by transcytosis. However, Brock et al., (2002) demonstrated that CpbA

mediated invasion is only found in Detroit-562 cell line and therefore, suggested thmediated pneumococcal invasion is strain and cell specific. CbpA is highly polymorphic (Iannelli and there is substantial strain to strain variation in S. pneumoniae and this influences virulence (Kerr

In addition to a virulence role in adherence and invasion, CbpA is also involved in S. pneumoniaecomplement by binding to factor H (Dave et al., 2001; Kerr et al., 2006). Factor is a serum protein that impedes

lement component 3b (C3b) and therefore, prevents host cells from being attacked by its own complement pathway (Dave et al., 2001; Jarva et al., 2003). It can be deduced that by binding pneumococcal CbpA, factor H is then able to bind C3b deposited on the cell surface, thereby arresting the complement pathway at this crucial phase. In addition, CbpA could decrease alternative pathway activity by modulating the rate of C3 degradation to iC3b, causing dissociation of factor B (Bf) from the C3 convertase

ing C3b deposition, or inhibiting C3bBb formation by preferentially binding C3b.

CbpA is a potential vaccine candidate as a result of its role in carriage and pathogenesis. Furthermore, the CbpA is extends beyond the capsule and therefore, carriage can be abolished by either opsonic or neutralizing antibodies. Reports of immunization studies indicate that CbpA can be highly protective against

peritoneal challenge (Brooks-Walter et al., 1999; Ogunniyi et al., 2001

The toxigenic potential of pneumolysin (Ply) in the pathogenesis of pneumococcal disease has been demonstrated and it is found in practically all clinical isolates of S. pneumoniae (Paton et altoxigenic potential lies on its interaction of the cell membranes which results in transmembrane pore formation allowing the influx of water, ions and some organic macromolecules, culminating to cell lysis (Boulnois

, it has been proposed that Ply may also induce upregulation of nitric oxide production by macrophages causing damage to the host’s cells (Braun et al., 1999; Braun et al., 2000). Furthermore, Ply has been shown to cause activation of the classical pathway of complement system in the absence of specific antibody through binding of C1 to Ply domain which is common to the Fc portion of IgG (Paton

., (2003) demonstrated that the growth of S. pneumoniae blood is as a result of complement activating property of Ply. Various studies have shown the association of Ply and pneumococcal septicaemia, and reduction in replication and survival in the blood of an animal model was

ant strains (Benton et al., 1995; Berry et al., 1999).

The alteration of the plasma membrane integrity by ply has been shown to stimulate the production and release by neutrophils (Cockeran et al., 2002). In addition, reports indicate that Ply

-1β, and IL-6 by blood monocytes (Houldsworth et al., 1994). It can be deduced that the induction of inflammatory responses might be a contributing factor to the severity opneumococcal disease and the high mortality rate. Furthermore, Ply has been demonstrated to inhibit the beating of the cilia lining the respiratory epithelium increasing the accumulation of the bacteria in the lung which may

et al., 1991). It is likely that Ply has multiple roles in pneumococcal pathogenesis, and further research is needed to unlock these other roles.

The pneumococcus produces large proteases on its surface which are mainly zinc lloproteinases and previously sequenced genomes showed that four can be found in an isolate (Chiavolini

., 2003). These are frequently associated with invasive infections and virulence in serotype 4 pneumococci, but not associated with virulence in serotype 3 pneumococci and only two are important for virulence in

., 2003). The IgA1 protease and ZmpC are the only zinc metalloproteinases that

allow the pneumococcus to evade host mucosal immunoglobulin which explains its substantial diversity as it is required to cleave structurally diverse substrates (Poulsen To cleave structurally diverse substrates, pneumococcal strains show variation in the number and sequence of


nding to the human polymeric immunoglobin receptor (pIgR) ., (2002) demonstrated that CpbA-

562 cell line and therefore, suggested that CpbA-pIgR-mediated pneumococcal invasion is strain and cell specific. CbpA is highly polymorphic (Iannelli et al., 2002)

e and this influences virulence (Kerr et al.,

S. pneumoniae evasion of ., 2006). Factor is a serum protein that impedes

lement component 3b (C3b) and therefore, prevents host cells from being ., 2003). It can be deduced that by

cell surface, thereby arresting the complement pathway at this crucial phase. In addition, CbpA could decrease alternative pathway activity by modulating the rate of C3 degradation to iC3b, causing dissociation of factor B (Bf) from the C3 convertase

CbpA is a potential vaccine candidate as a result of its role in carriage and pathogenesis. Furthermore, the CbpA abolished by either opsonic or neutralizing

antibodies. Reports of immunization studies indicate that CbpA can be highly protective against S. pneumoniae ., 2001).

The toxigenic potential of pneumolysin (Ply) in the pathogenesis of pneumococcal disease has been et al., 1993). Its

toxigenic potential lies on its interaction of the cell membranes which results in transmembrane pore formation allowing the influx of water, ions and some organic macromolecules, culminating to cell lysis (Boulnois et al.,

, it has been proposed that Ply may also induce upregulation of nitric oxide production by ., 2000). Furthermore, Ply has

of complement system in the absence of specific antibody through binding of C1 to Ply domain which is common to the Fc portion of IgG (Paton et al., 1984;

in the lung and blood is as a result of complement activating property of Ply. Various studies have shown the association of Ply and pneumococcal septicaemia, and reduction in replication and survival in the blood of an animal model was

The alteration of the plasma membrane integrity by ply has been shown to stimulate the production and release ., 2002). In addition, reports indicate that Ply

., 1994). It can be deduced that the induction of inflammatory responses might be a contributing factor to the severity of pneumococcal disease and the high mortality rate. Furthermore, Ply has been demonstrated to inhibit the beating of the cilia lining the respiratory epithelium increasing the accumulation of the bacteria in the lung which may

., 1991). It is likely that Ply has multiple roles in pneumococcal

lloproteinases and previously sequenced genomes showed that four can be found in an isolate (Chiavolini et ., 2003). These are frequently associated with invasive infections and virulence in serotype 4 pneumococci,

rotype 3 pneumococci and only two are important for virulence in ., 2003). The IgA1 protease and ZmpC are the only zinc metalloproteinases that

ccus to evade host mucosal immunoglobulin which explains its substantial diversity as it is required to cleave structurally diverse substrates (Poulsen et al., 1998).

ber and sequence of


Ukpai A. Eze et al.,: repeat regions to facilitate (Poulsen microarray DNA CGH experiments where failure to hybridize indicates substantial divergence from the probe on the microarray (Hakenbeck et al., 2001). The Zinc metalloproteinase C (ZmpC) (Oggioni et al., 2003). Reports indicate the absence of found in 26% of pneumococcal isolates from patients with pneumonia (Chiavolini not detected in isolates from nasal or conjunctival swab (Oggioni that ZmpC is associated with pneumococcal virulence and pathogenicity in the lung Two-component signal transduction systems The two-components signal transduction systems (TCS) consists of a membrane associated sensor, histidine kinase (HK) which on receipt of a specific stimulus phosphorylates an aspartate residue in a cytoplasmic cognate response regulator (RR) which invariabal., 2006). It regulates various cellular processes in bacteria such as osmoregulation, sporulation, genetic competence and chemotaxis. The TCS allow pneumococci to respond to changes inet al., 2006). Currently, thirteen TCS and one orphan response regulator have been found in the pneumococcus (Paterson et al., 2006). The most studied TCS in an important virulence factor. ComD is associated with pneumonia and bacteriaemia in serotype 2 strain D39, serotype 3 strain 0100993 and serotype 4 strain TIGR4 (Paterson contribution of TCS to virulence varies depending microarray analysis have given new insights into gene regulation of TCS, the understanding of their interaction remain largely unclear. Pneumococcal pilus A pneumococcal pilus (PI-1 and PI-2) is encofor three pilus subunits (RrgA, RrgB and RrgC) and can be found in some but not all pneumococcal isolates (Paterson and Mitchell, 2006) where it has a role in adherence and may be involved al., 2006; Gianfaldoni et al., 2007). PIdocumented as absent from serotypes 1, 7F, 8 and 12B and its presence appears to be a clonal property (Moschioni et al., 2008) where it is particularly associated with ST156 and ST162 (Sjostrom contrast, Turner et al., (2011) reported that PIserotypes, including 4, 6A, 6B, 9, 14, 19F, 19A, 23F,common in in 19F (91%) and 23F (77%). In addition, Moschioni media clinical isolates from Israel detected PI1 in 6A, 6B, 14, 19F, 23F, 33A and 11A, whereas PI2010). Pillus antigens should be properly evaluated as they are currently regarded as potential candidate for inclusion in a protein-based pneumococcal vaccine. Pyruvate oxidase (SpxB) SpxB encodes a pyruvate oxidase that catalyses the reduction of pyruvate, free phosphate and oxygen to form carbon dioxide, acetylphosphate and hydrogen peroxide (Johnston major virulence factor in S. pneumoniae (Spellerberg highly expressed in environments rich in both oxygen and carbon (IV) oxide, conditions which are perculiar to the nasopharynx. The formation of hydrogen peroxide inhibits the growth of competing microflora, including Haemophilus influenzae, Neisseria meningitides and Moraxella catarhalis, and may also enhance pneumococcal adherence to nasopharyngeal epithelium and progression to th2004). In addition, production of hydrogen peroxide during infection promotes inflammation and cell damage, and induces TLR-2 and TLR-4 independent apoptosis in the brain epithelial cells. This results to nedamage and brain cell mitochondrial damage, and SpxB is implicated in pneumococcal meningitis. Furthermore, SpxB also enhances pneumococcal resistance to hydrogen peroxide and this allows it to grow in high hydrogen peroxide concentrations than many LeMessurier et al., (2006) demonstrated that brain in WCH16 strain intraperitoneal challenge in a mouse model. The presence of SpxB might be the cause of increased nasopharyngeal carriage of Streptococcus pneumoniae


33


repeat regions to facilitate (Poulsen et al., 1998). This high level of diversity has been demonstrated in microarray DNA CGH experiments where failure to hybridize indicates substantial divergence from the probe

., 2001).

The Zinc metalloproteinase C (ZmpC) specifically cleaves human matrix metalloproteinase 9 (MMP., 2003). Reports indicate the absence of ZmpC in R6 genome (Chiavolini et al

found in 26% of pneumococcal isolates from patients with pneumonia (Chiavolini et al., 2003) whereas it was not detected in isolates from nasal or conjunctival swab (Oggioni et al., 2003). Oggioni et al., (2003) proposed

is associated with pneumococcal virulence and pathogenicity in the lung

component signal transduction systems components signal transduction systems (TCS) consists of a membrane associated sensor, histidine

kinase (HK) which on receipt of a specific stimulus phosphorylates an aspartate residue in a cytoplasmic cognate response regulator (RR) which invariably results in alteration of levels of gene transcription (Paterson

., 2006). It regulates various cellular processes in bacteria such as osmoregulation, sporulation, genetic competence and chemotaxis. The TCS allow pneumococci to respond to changes in their environment (Paterson

., 2006). Currently, thirteen TCS and one orphan response regulator have been found in the pneumococcus ., 2006). The most studied TCS in S. pneumoniae is the competence gene (comDE

nt virulence factor. ComD is associated with pneumonia and bacteriaemia in serotype 2 strain D39, serotype 3 strain 0100993 and serotype 4 strain TIGR4 (Paterson et al., 2006; Hendriksen et alcontribution of TCS to virulence varies depending on S. pneumoniae strain and site of infection. Although microarray analysis have given new insights into gene regulation of TCS, the understanding of their interaction

2) is encoded by the rlrA islet (LeMieux et al., 2006), which includes genes for three pilus subunits (RrgA, RrgB and RrgC) and can be found in some but not all pneumococcal isolates (Paterson and Mitchell, 2006) where it has a role in adherence and may be involved in virulence (Barocchi

., 2007). PI-1 is associated with serotypes 4, 6B, 9V and 14 while it has been documented as absent from serotypes 1, 7F, 8 and 12B and its presence appears to be a clonal property

08) where it is particularly associated with ST156 and ST162 (Sjostrom ., (2011) reported that PI-1 was present in 35.2 % of pneumococcal isolates occurring in 10

serotypes, including 4, 6A, 6B, 9, 14, 19F, 19A, 23F, 33C and non-typeable pneumococci (NT) and PIcommon in in 19F (91%) and 23F (77%). In addition, Moschioni et al., (2010) in a research involving otitis media clinical isolates from Israel detected PI-1 in 30.1 % and PI-2 in 7 % of the isolates tested. They found PI1 in 6A, 6B, 14, 19F, 23F, 33A and 11A, whereas PI-2 was detected in serotype 19F only (Moschoioni 2010). Pillus antigens should be properly evaluated as they are currently regarded as potential candidate for

based pneumococcal vaccine.

encodes a pyruvate oxidase that catalyses the reduction of pyruvate, free phosphate and oxygen to form carbon dioxide, acetylphosphate and hydrogen peroxide (Johnston et al., 2004). SpxB has been dmajor virulence factor in S. pneumoniae (Spellerberg et al., 1996). Pericone et al., (2000) reported that highly expressed in environments rich in both oxygen and carbon (IV) oxide, conditions which are perculiar to

he formation of hydrogen peroxide inhibits the growth of competing microflora, including Haemophilus influenzae, Neisseria meningitides and Moraxella catarhalis, and may also enhance pneumococcal adherence to nasopharyngeal epithelium and progression to the lungs (Pericone et al., 2000; Orihuela 2004). In addition, production of hydrogen peroxide during infection promotes inflammation and cell damage,

4 independent apoptosis in the brain epithelial cells. This results to nedamage and brain cell mitochondrial damage, and SpxB is implicated in pneumococcal meningitis. Furthermore, SpxB also enhances pneumococcal resistance to hydrogen peroxide and this allows it to grow in high hydrogen

other bacteria colonizing the nasopharynx (Pericone ., (2006) demonstrated that SpxB gene is found in high concentration in the nasopharynx and

brain in WCH16 strain intraperitoneal challenge in a mouse model. The presence of SpxB might be the cause of Streptococcus pneumoniae globally.


., 1998). This high level of diversity has been demonstrated in microarray DNA CGH experiments where failure to hybridize indicates substantial divergence from the probe

fically cleaves human matrix metalloproteinase 9 (MMP-9) et al., 2003). It was

) whereas it was ., (2003) proposed

components signal transduction systems (TCS) consists of a membrane associated sensor, histidine kinase (HK) which on receipt of a specific stimulus phosphorylates an aspartate residue in a cytoplasmic

ly results in alteration of levels of gene transcription (Paterson et ., 2006). It regulates various cellular processes in bacteria such as osmoregulation, sporulation, genetic

their environment (Paterson ., 2006). Currently, thirteen TCS and one orphan response regulator have been found in the pneumococcus

comDE) system and is nt virulence factor. ComD is associated with pneumonia and bacteriaemia in serotype 2 strain D39,

et al., 2007). The strain and site of infection. Although

microarray analysis have given new insights into gene regulation of TCS, the understanding of their interaction

., 2006), which includes genes for three pilus subunits (RrgA, RrgB and RrgC) and can be found in some but not all pneumococcal isolates

in virulence (Barocchi et 1 is associated with serotypes 4, 6B, 9V and 14 while it has been

documented as absent from serotypes 1, 7F, 8 and 12B and its presence appears to be a clonal property 08) where it is particularly associated with ST156 and ST162 (Sjostrom et al., 2007). In

1 was present in 35.2 % of pneumococcal isolates occurring in 10 typeable pneumococci (NT) and PI-1 was

., (2010) in a research involving otitis d. They found PI-

2 was detected in serotype 19F only (Moschoioni et al., 2010). Pillus antigens should be properly evaluated as they are currently regarded as potential candidate for

encodes a pyruvate oxidase that catalyses the reduction of pyruvate, free phosphate and oxygen to form ., 2004). SpxB has been described as a

., (2000) reported that SpxB is highly expressed in environments rich in both oxygen and carbon (IV) oxide, conditions which are perculiar to

he formation of hydrogen peroxide inhibits the growth of competing microflora, including Haemophilus influenzae, Neisseria meningitides and Moraxella catarhalis, and may also enhance pneumococcal

., 2000; Orihuela et al., 2004). In addition, production of hydrogen peroxide during infection promotes inflammation and cell damage,

4 independent apoptosis in the brain epithelial cells. This results to neuronal damage and brain cell mitochondrial damage, and SpxB is implicated in pneumococcal meningitis. Furthermore, SpxB also enhances pneumococcal resistance to hydrogen peroxide and this allows it to grow in high hydrogen

other bacteria colonizing the nasopharynx (Pericone et al., 2003). gene is found in high concentration in the nasopharynx and

brain in WCH16 strain intraperitoneal challenge in a mouse model. The presence of SpxB might be the cause of


Ukpai A. Eze et al.,: Pneumococcal surface antigen A Pneumococcal surface antigen (PsaA) is the third gene in the lipoprotein receptor-associated antigen family (Johnston bacteria involved in in the transport of Mnhave shown the presence of PsaA gene in all the 90 pneumococcal serotypes using PCR technique (Morrison al., 2000). Manganese acts as a cofactor for bacterial proteins involved in glycolysis, gluconeogenesis, sugar and amino acid metabolism, peptide cleavage, nucleic acid degradation, signal transduction, and oxidative stress defence, and has been shown to contribute to bacterial survival and growth during infection (Jedrzejas, 2004). In addition, Mutants that lack PsaA failed to establish coin vivo models, which may be as a result of low concentrations of Mn2+ in these locations (McAllister 2004). PsaA gene was found in high level the blood of a mice model challenged with D39 been suggested to be involved in pneumococcal septicaemia (LeMessurier also found in Streptococcus mitis, Streptococcus oralisfunction in these bacteria is still unclear. Intranasal immunisation of mice with PsaA has been reported to protect against pneumococcal carriage in the nasopharynx (Briles cholera toxin B subunit-PsaA fusion protein protected mice against pneumococcal colonisation after intranasal immunisation (Pimenta et al., 2006). These studies indicate that PsaA is a potential musal vaccine candidate. Other virulence factors PsaR has been shown to contribute to the survival of pneumococci during bacteraemia. PsaR is mediate its activity through Psa operon, PcpA, and has been reported to be responsible for the regulation of Manganese which is physiology and virulence (Hendriksen et alvirulence of a serotype 3 in bacteraemia model of infection after 24 hours of infection. Similarly, PsaR does not contribute to nasopharyngeal colonisation, but it is involved in invasive disease where it has strainimpact during both pneumonia and bacteraemia (Hendriksen activated by codY and is required for adnutritional regulation and adherence (Hendriksen pathogenesis remains unclear. GlnA gene, a glutamate synthase, catalyses the gene is the major glutamine/glutamate ABC transporter. Recently, it was described that are involved in pneumococcal adhesion to human nasopharyngeal cells, which is a prehost (Kloosterman et al., 2006). In a mouse model, GlnA was shown to be associated with colonisation and GlnP for bacterial survival in the lungs, and a glnA2008b). In addition, glnP double mutant was unable to reach the systemic circulation in a mouse model, indicating that glnP is involved the dissemination of possible that a vaccine against glnP may be able to eliminate pnoligopeptide ABC transporter, Ami/Ali permease is associated with adherence, through direct interaction with human receptors or upregulating pneumococcal adhesins (Cundell al., 2007; Hendriksen et al., 2008b). It is essential for a successful nasopharyngeal colonisation in a mice model, and was not involved in invasive disease. Autolysins are also implicated in pneumococcal virulence. They are group of enzymes capable of dbacterial peptidoglycan leading to cell lysis. Several autolysins have been identified in autolysin A (LytA), autolysin B (LytB) and Autolysin C, LytC (Garcia LytA is the major pneumococcal autolysin and causes the autolysis of bacterial cell wall peptidoglycan, and also mediate the release of pneumolysin (Martner factor A (PavA), a fibronectin adhesion have been demonstraand adherence to nasopharyngeal cells, invasion, and Modulation of meningeal inflammation, but its mechanism of action still remain unclear (Homes further understanding of these factors will help to clarify pneumococcal factors which favour adherence.


34


) is the third gene in the psa operon, a lipoprotein which is related to the associated antigen family (Johnston et al., 2004). It is part of the transport system in

bacteria involved in in the transport of Mn2+ and Zn2+ into the cell (Jedrzejas, 2004). Morrison andgene in all the 90 pneumococcal serotypes using PCR technique (Morrison

., 2000). Manganese acts as a cofactor for bacterial proteins involved in glycolysis, gluconeogenesis, sugar peptide cleavage, nucleic acid degradation, signal transduction, and oxidative stress

defence, and has been shown to contribute to bacterial survival and growth during infection (Jedrzejas, 2004). In addition, Mutants that lack PsaA failed to establish colonisation, cause pneumonia, bateraemia or otitis media in

models, which may be as a result of low concentrations of Mn2+ in these locations (McAllister gene was found in high level the blood of a mice model challenged with D39 and WCH16, and has

been suggested to be involved in pneumococcal septicaemia (LeMessurier et al., 2006). However, Streptococcus oralis and Streptococcus anginosus (Jado et al

function in these bacteria is still unclear. Intranasal immunisation of mice with PsaA has been reported to protect against pneumococcal carriage in the nasopharynx (Briles et al., 2000; Johnson et al

PsaA fusion protein protected mice against pneumococcal colonisation after intranasal ., 2006). These studies indicate that PsaA is a potential musal vaccine candidate.

to the survival of pneumococci during bacteraemia. PsaR is mediate its , and PrtA and is majorly found in TIGR4 and D39 pneumococcal strains. It

has been reported to be responsible for the regulation of Manganese which is required for pneumococcal et al., 2009). Lau et al., (2001) demonstrated that PsaR is required for full

virulence of a serotype 3 in bacteraemia model of infection after 24 hours of infection. Similarly, PsaR does not ontribute to nasopharyngeal colonisation, but it is involved in invasive disease where it has strain

impact during both pneumonia and bacteraemia (Hendriksen et al., 2009). Choline binding protein (PcaA) is activated by codY and is required for adherence to nasopharyngeal cells, indicating a relationship between nutritional regulation and adherence (Hendriksen et al., 2008a), but the exact role of of PcaA in pneumococcal

gene, a glutamate synthase, catalyses the formation of glutamine from glutamate and ammonia, and gene is the major glutamine/glutamate ABC transporter. Recently, it was described that GlnP are involved in pneumococcal adhesion to human nasopharyngeal cells, which is a pre-requisite to invade the

., 2006). In a mouse model, GlnA was shown to be associated with colonisation and GlnP for bacterial survival in the lungs, and a glnA-glnP double mutant lost its virulence (Hendriksen

glnP double mutant was unable to reach the systemic circulation in a mouse model, indicating that glnP is involved the dissemination of S. pneumoniae from the lungs to the blood stream. It is possible that a vaccine against glnP may be able to eliminate pneumococcal septicaemia Furthermore, the oligopeptide ABC transporter, Ami/Ali permease is associated with adherence, through direct interaction with human receptors or upregulating pneumococcal adhesins (Cundell et al., 1995; Kerr et al., 2004; Anderton

., 2008b). It is essential for a successful nasopharyngeal colonisation in a mice model, and was not involved in invasive disease.

Autolysins are also implicated in pneumococcal virulence. They are group of enzymes capable of dbacterial peptidoglycan leading to cell lysis. Several autolysins have been identified in S. pneumoniaeautolysin A (LytA), autolysin B (LytB) and Autolysin C, LytC (Garcia et al., 1999; Hendriksen

ococcal autolysin and causes the autolysis of bacterial cell wall peptidoglycan, and also mediate the release of pneumolysin (Martner et al., 2008). Similarly, pneumococcal adherence and virulence factor A (PavA), a fibronectin adhesion have been demonstrated to be involved in pneumococcal colonization and adherence to nasopharyngeal cells, invasion, and Modulation of meningeal inflammation, but its mechanism of action still remain unclear (Homes et al., 2001; Pracht et al., 2005; Rajam et al., 2008). It isfurther understanding of these factors will help to clarify pneumococcal factors which favour adherence.


operon, a lipoprotein which is related to the ., 2004). It is part of the transport system in

into the cell (Jedrzejas, 2004). Morrison and colleagues gene in all the 90 pneumococcal serotypes using PCR technique (Morrison et

., 2000). Manganese acts as a cofactor for bacterial proteins involved in glycolysis, gluconeogenesis, sugar peptide cleavage, nucleic acid degradation, signal transduction, and oxidative stress

defence, and has been shown to contribute to bacterial survival and growth during infection (Jedrzejas, 2004). In lonisation, cause pneumonia, bateraemia or otitis media in

models, which may be as a result of low concentrations of Mn2+ in these locations (McAllister et al., and WCH16, and has

., 2006). However, PsaA gene is et al., 2001), but its

function in these bacteria is still unclear. Intranasal immunisation of mice with PsaA has been reported to et al., 2002) and a

PsaA fusion protein protected mice against pneumococcal colonisation after intranasal ., 2006). These studies indicate that PsaA is a potential musal vaccine candidate.

to the survival of pneumococci during bacteraemia. PsaR is mediate its and is majorly found in TIGR4 and D39 pneumococcal strains. It

required for pneumococcal ., (2001) demonstrated that PsaR is required for full

virulence of a serotype 3 in bacteraemia model of infection after 24 hours of infection. Similarly, PsaR does not ontribute to nasopharyngeal colonisation, but it is involved in invasive disease where it has strain-specific

., 2009). Choline binding protein (PcaA) is herence to nasopharyngeal cells, indicating a relationship between

., 2008a), but the exact role of of PcaA in pneumococcal

formation of glutamine from glutamate and ammonia, and GlnP and GlnA genes site to invade the

., 2006). In a mouse model, GlnA was shown to be associated with colonisation and glnP double mutant lost its virulence (Hendriksen et al.,

glnP double mutant was unable to reach the systemic circulation in a mouse model, from the lungs to the blood stream. It is

eumococcal septicaemia Furthermore, the oligopeptide ABC transporter, Ami/Ali permease is associated with adherence, through direct interaction with

., 2004; Anderton et ., 2008b). It is essential for a successful nasopharyngeal colonisation in a mice model,

Autolysins are also implicated in pneumococcal virulence. They are group of enzymes capable of degrading S. pneumoniae including,

., 1999; Hendriksen et al., 2009). ococcal autolysin and causes the autolysis of bacterial cell wall peptidoglycan, and also

., 2008). Similarly, pneumococcal adherence and virulence ted to be involved in pneumococcal colonization

and adherence to nasopharyngeal cells, invasion, and Modulation of meningeal inflammation, but its mechanism ., 2008). It is hoped that

further understanding of these factors will help to clarify pneumococcal factors which favour adherence.


Ukpai A. Eze et al.,:

Figure 1.2: Interaction between S pneumoniae viscosity of the mucus and exposes the Ncan interact with pneumococcal surfacehost epithelial cells upregulate the plateletaffinity via its cell-wall phosphocholine (ChoP) for PAFr. Moreover, a second cholineshows increased affinity for immobilised sialic acid and lactoIg receptor (pIgR), which increases migration through the mucosal barrier (transcytosis). Pneumococcal IgA1protease cleaves opsonising IgA, which results ithe physical proximity of ChoP to the PAFr. Adapted from:

Figure 1.3: A representsation of the cell membrane, cell wall, and capsule of (Musher, 2005) CONCLUSION A thorough understanding of pneumococcal components necessary for pathogenicity and virulence is required to combat pneumococcal disease. Until recently, the capsule has been the major focus of pneumococcal vaccine. However, recent advances in the understanding of the structure and function of various pathogenicity and virulence factors have paved way for the possibility of developing protein vaccines. The introduction of proteinbased pneumococcal vaccine comprising surface


35


S pneumoniae and epithelial cells. Neuraminidase (NanA) decreases the

viscosity of the mucus and exposes the N-acetyl-glycosamine (GlcNAc) receptors on the epithelial cells, which can interact with pneumococcal surface-associated proteins such as PsaA. In response to cytokine stimulation, host epithelial cells upregulate the platelet-activating-factor receptors (PAFr). The pneumococcus has increased

wall phosphocholine (ChoP) for PAFr. Moreover, a second choline-binding protein, CbpA, ed affinity for immobilised sialic acid and lacto-N-neotreatose, and binds directly to the polymeric

Ig receptor (pIgR), which increases migration through the mucosal barrier (transcytosis). Pneumococcal IgA1protease cleaves opsonising IgA, which results in a change (neutralisation) of surface charge and increases the physical proximity of ChoP to the PAFr. Adapted from: (Bogaert et al., 2004).

Figure 1.3: A representsation of the cell membrane, cell wall, and capsule of S.pneumoniae. Adapted from:

A thorough understanding of pneumococcal components necessary for pathogenicity and virulence is required to combat pneumococcal disease. Until recently, the capsule has been the major focus of pneumococcal vaccine.

nt advances in the understanding of the structure and function of various pathogenicity and virulence factors have paved way for the possibility of developing protein vaccines. The introduction of proteinbased pneumococcal vaccine comprising surface-exposed proteins associated with nasopharyngeal colonisation


and epithelial cells. Neuraminidase (NanA) decreases the glycosamine (GlcNAc) receptors on the epithelial cells, which

ytokine stimulation, factor receptors (PAFr). The pneumococcus has increased

binding protein, CbpA, neotreatose, and binds directly to the polymeric

Ig receptor (pIgR), which increases migration through the mucosal barrier (transcytosis). Pneumococcal n a change (neutralisation) of surface charge and increases

Adapted from:

A thorough understanding of pneumococcal components necessary for pathogenicity and virulence is required to combat pneumococcal disease. Until recently, the capsule has been the major focus of pneumococcal vaccine.

nt advances in the understanding of the structure and function of various pathogenicity and virulence factors have paved way for the possibility of developing protein vaccines. The introduction of protein-

ed proteins associated with nasopharyngeal colonisation


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STREPTOCOCCUS PNEUMONIAE: VIRULENCE FACTORS AND THEIR ROLE IN PATHOGENESIS.

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