Humans and Microbes • Since Leeuwenhoek’s discovery of microorganisms in 17 th century led people to suspect they might cause diseases, most research and funding has gone towards understanding pathogens. • Robert Koch (1876) offered proof of what is now considered germ theory of disease; showed Bacillus anthracis causes anthrax • Today, we now know that most of the bacteria we associate with are not pathogens, and many are critical for our health.
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Humans and Microbes Since Leeuwenhoek’s discovery of microorganisms in 17 th century led people to suspect they might cause diseases, most research and.
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Humans and Microbes
• Since Leeuwenhoek’s discovery of microorganisms in 17th century led people to suspect they might cause diseases, most research and funding has gone towards understanding pathogens.
• Robert Koch (1876) offered proof of what is now considered germ theory of disease; showed Bacillus anthracis causes anthrax
• Today, we now know that most of the bacteria we associate with are not pathogens, and many are critical for our health.
Bacteria Are Ubiquitous
We contact numerous microorganisms daily• Breathe in, ingest, pick up on skin• Vast majority do not make us sick, or cause infections• Some colonize body surfaces; or slough off with dead
epithelial cells• Most that are swallowed die in stomach or are
eliminated in feces• Relatively few are pathogens that
cause damage
Microbes, Health, and Disease
Most microbes are harmless• Many are beneficial• Normal microbiota (normal flora) are organisms that
routinely reside on body’s surfaces• Relationship is a balance, and some can cause disease
under certain conditions-- opportunistic infections
• Weaknesses in innate or adaptive defenses can leave individuals vulnerable to invasion
– malnutrition, cancer, AIDS or other disease, surgery, wounds, genetic defects, alcohol or drug abuse, and immunosuppressive therapy
The Anatomical Barriers as Ecosystems
Skin, mucous membranes are barriers• Also host complex ecosystem of microorganisms
• Example of symbiosis, or “living together”
• Mutualism: both partners benefit
– In large intestine, bacteria synthesize vitamin K and B’s, which host can absorb; bacteria are supplied with warmth, energy sources
• Commensalism: one partner benefits, other is unharmed
– Many microbes living on skin neither harmful nor helpful, but obtain food and necessities from host
• Parasitism/pathogenicity: one organism benefits at expense of other
– pathogens and parasites
Human commensals and mutalistic microbes
Resident microbiota inhabit sites for extended periods
Transient microbiota inhabit temporarily
• Important to human health• Relatively little is known• Human Microbiome
Project aimed at studyinghttp://en.wikipedia.org/wiki/
The Protective Role of the Normal Microbiota• Significant contribution is protection against pathogens
• Covering of binding sites prevents attachment
• Consumption of available nutrients
• Production of compounds toxic to other bacteria
• When killed or suppressed (e.g., during antibiotic treatment), pathogens may colonize, cause disease
• Some antibiotics inhibit Lactobacillus (predominate vagina of mature females, suppress growth of Candida albicans); results in vulvovaginal candidiasis
• Oral antibiotics can inhibit intestinal microbiota, allow overgrowth of toxin-producing Clostridium difficile
The Normal Microbiota
The Protective Role of the Normal Microbiota (continued…)• Stimulation of adaptive immune system-CRITICAL
• Mice reared in microbe-free environment have greatly underdeveloped mucosal-associated lymphoid tissue (MALT); antibodies against normal microbiota bind to pathogens as well
• Important in development of oral tolerance• Immune system learns to lessen response to many
microbes that routinely inhabit gut as well as food
– Basis of hygiene hypothesis, which proposes insufficient exposure to microbes can lead to allergies
The Normal Microbiota
The Dynamic Nature of the Normal Microbiota• Healthy human fetus sterile until just before birth
• Exposure during birth and through contact with people, food, and environment lead to microbes becoming established on
• find that families often share similar microbial populations, and important gut microbes are acquired from the mother
• Critical for proper gut development—first colonizers from mom
• Composition of normal microbiota is dynamic• Changes occur over the life of a person. Younger people tend
to have different compositions than older people. • Responses to physiological changes (e.g., hormonal changes),
activities and diet (e.g., consuming food)
Microbiota alter the chemistry of your gutRuth Ley, Peter Turnbaugh, Jeffrey Gordon and colleagues at Washington University link between the microbiota and obesity by studying a special strain-Obese mice had 50% fewer Bacteroidetes and 50% more Firmicutes in their bowels than their lean counterparts.
The link between the microbiota and obesity became even clearer when Gordon looked at a special strain of mice with no microbiota of their own.
When the team transplanted the microbiota from fat and lean mice into the germ-free strains, those colonized by microbiota from fat donors packed on far more weight than those paired with lean donors.
Comparisons of microbiota of fat and lean mice at a genetic level: --fat mice showed much stronger activation of genes for carbohydrate-destroying enzymes, which break down otherwise indigestible starches and sugars. As a result, these mice were extracting more energy from their food than their lean cousins.
The bacteria were also manipulating the animals’ own genes, --triggered biochemical pathways that store fats in the liver and muscles, rather than metabolize them.
Fat Bacteria Thin bacteriaMore Firmicutes More Bacteroidetes
--break down carbohydrates better
--trigger biochemical pathways to store fat
Principles of Infectious Disease
Key Terms.
Colonization--microbe establishes on body surface internal or external
• Infection usually refers to pathogen• subclinical: no or mild symptoms
• Infectious disease shows noticeable impairment
– Symptoms are subjective effects experienced by patient (e.g., pain and nausea)
– Signs are objective evidence (e.g., rash, pus formation, swelling)
• Initial infection is primary infection
– Damage can predispose individual to developing a secondary infection (e.g., respiratory illness impairing mucociliary escalator)
Fig. 24.1
Oral cavity containingtongue and teethDental cariesPeriodontal disease
Produces cytotoxins• Member of gut microbiome, in low
numbers, --It most commonly occurs in patients
in hospitals on antibiotic therapy.
• Can also be acquiredDifficult to kill with disinfectants (spores)
• Mild to severe symptoms including colitis (inflammation of the colon).
• Treatment: Often stopping the antibiotics, if possible, alleviates the problem.
This is a secondary infection
Principles of Infectious Disease
Pathogenicity• Primary pathogen is microbe or virus that causes
disease in otherwise healthy individual• Diseases such as plague, malaria, measles, influenza,
diphtheria, tetanus, tuberculosis, etc.
• Opportunistic pathogen (opportunist) causes disease only when body’s innate or adaptive defenses are compromised or when introduced into unusual location
• Can be members of normal microbiota or common in environment (e.g., Pseudomonas; E. coli; C. difficile)
• Virulence refers to degree of pathogenicity• Virulence factors are traits that allow microorganism
to cause disease
16.3. Principles of Infectious Disease
Characteristics of Infectious Disease• Communicable or contagious diseases easily spread• Infectious dose is number of microbes necessary to
establish infection• ID50 is number of cells that infects 50% of population
• Shigellosis results from ~10–100 ingested Shigella
• Salmonellosis results from as many as 106 ingested Salmonella enterica serotype Enteritidis
– Difference partially reflects ability to survive stomach acid
Course of Infectious Disease
• Incubation period: time between infection and onset• Illness: signs and symptoms of disease
• May be preceded by prodromal phase (vague symptoms)
• Convalescence: recuperation, recovery from disease• Carriers may harbor and spread infectious agent for
long periods of timeIncubation period ConvalescenceIllness
Acute. Illness is short term because the pathogen is eliminated by the hostdefenses; person is usually immune to reinfection.
Incubation period
Chronic. Illness persists over a long time period.
Incubation period
Latent. Illness may recur if immunity weakens.
Illness Convalescence Latency Recurrence
Illness (long lasting)
• Acute: • Rapid onset
• Short duration
• Persistent/chronic:• May develop slowly,
Continue foryears or lifetime
• May or may nothave symptoms
• Latent infections: never completely eliminated; may reactivate
Acute and Persistent Infections
State of VirusVirus disappearsafter disease ends.
State of VirusAfter initial infection with or without disease symptoms, infectious virus is released from host with no symptoms.
State of VirusAfter initial infection, virus is maintained in neurons in non-infectious state. Virusactivated to produce new disease symptoms.
Adherence• Adhesins attach to host cell receptor• Often on tips of pili (or fimbriae)• Can be component of capsules or various cell wall proteins• Binding highly specific; exploits host cell receptor
Colonization• Growth in biofilms• Siderophores-bind iron• Avoidance of secretory IgA• Rapid pili turnover-shed the IgA,
antigenic variations—avoid detection, IgA proteases—cut IgA
• Compete with normalmicrobiota, tolerate toxins
Invasion—Breaching the Anatomical Barriers
Penetrating the Skin• Difficult barrier to penetrate; bacteria rely on injuries
• Staphylococcus aureus enters via cut or wound; Yersinia pestis is injected by fleas, Lyme’s disease by tick bite
Penetrating Mucous Membranes-respiratory and gut tracts
• CommoneEntry point pathogens• Directed Uptake by Cells
• Pathogen induces cells to engulf via endocytosis
– Salmonella uses type III secretion system to injecteffector proteins; actin molecules rearrange, yieldmembrane ruffling
Courtesy of Mark A. Jepson, from Trends in Microbiology v6, issue 1:359-365, 1 Sept 1998, "Studying M cells and their role in infection"; M.A. Jepson and M.A. Clark, Elsevier Press
Recall from CH 24 pathogensShigella, Salmonella, E. coli
Invasion—Penetrating mucus membranes
Salmonella attach to cells at the end of the small intestine
T3SS injects effectors and the cells are taken into cell in phagosomes.
These are transported across the cell and exported (exocytosis) where they are picked up by macrophage which are often destroyed. The infection remains localized. Inflammatory response results in fluid secretion.
Invasion—Penetrating mucus membranes
Exploiting Antigen-Sampling Processes of the Pyer’s patches (Mucosal-associated lymphoid tissue (MALT) and their M cells)
• Shigella survives phagocytosis bymacrophages; induces apoptosis; binds to base of mucosal epithelialcells and induces uptake. Salmonella typhae also.
• Some invade by alveolar(lung) macro-phages (e.g., Mycobacterium tuberculosis produces surfaceproteins, directs uptake, avoids macrophage activation)
Within an epithelial cell, Shigella cells causethe host actin to polymerize. This propelsthe bacterial cell, sometimes with enoughforce to push it into the next cell.
Mucousmembrane
Shigella cells attach to thebase of the epithelial cellsand induce these cells toengulf them.
Macrophages in the Peyer’s patches engulf material thatpasses through M cells. Shigella cells survive andreplicate, causing the phagocytes to undergo apoptosis.
Lumen of the intestine
Tissue
1
3
2
Macrophages
M cell
Shigella
Avoiding the Host Defenses
Hiding Within a Host Cell• Allows avoidance of complement proteins, phagocytes,
and antibodies• Shigella directs transfer from intestinal epithelial cell to
adjacent cells by causing host cell actin polymerization
• Listeria monocytogenes (meningitis) does the same
Avoiding Killing by Complement System Proteins• Serum resistant bacteria resist
C3b binding to microbial invaders Mannose-binding lectin (MBL) binding to microbial invaders
Antibodies binding to microbial invaders
OpsonizationC3b binds to microbial cells,functioning as an opsonin.Inflammatory response
C3a and C5a induce changes thatcontribute to local vascular permeabilityand attract phagocytes.
C3 Splits C3
C3bC3a
C5
C5a C5b
C3b
C9C9C9
C5b
C6Lysis of foreign cellsC5b combines with complementproteins C6, C7, C8, and C9to form membrane attackcomplexes that insertinto cell membranes.
Combines with C3convertase to form anenzyme that splits C5
C3b MBL
C9C8
C7
Triggered by Triggered byTriggered by
Formation of C3 convertase
The complement system revisited-pathogens have ways to avoid binding to the C3b, deactivating C5a and C5b to avoid attracting phagocytes or being attacked by the membrane attack complex (MACs). The MAC attack.
Adapted from Arousing the Fury of the Immune System, 1998 Howard Hughes Medical Institute.
Effector functions of Cytotoxic T cells
Exotoxins (continued…)
• Other Toxic Proteins• Some damaging proteins are not A-B toxins, membrane-
damaging toxins, or superantigens
• E.g., exfoliatin from Staphylococcus aureus causes scalded skin syndrome
– Destroys material that binds together skin layers
– Bacteria may be growing in small lesion, but toxin spreads systemically
• Various hydrolytic enzymes including proteases, lipases, and collagenases break down connective tissue
– Destroy tissues, some help bacteria spread
Damage to the Host
Endotoxin, Other Bacterial Cell Wall Components• Endotoxin is lipopolysaccharide (LPS)
• Lipid A triggers inflammatory response
– When localized, response helps clear
– When systemic, causes widespread response: septic shock or endotoxic shock
• Lipid A typically released following cell lysis
– Phagocytosis, MAC formation, certain antibiotics
• Activates innate and adaptive defenses
– Toll-like receptors (monocytes, macrophages, others) induce cytokine production; also T-independent antigen response of B-cells at high concentrations
• Heat-stable; autoclaving does not destroy
• Peptidoglycans, other components also trigger
Damaging Effects of the Immune Response
• Damage Associated with Inflammation• Phagocytic cells can release enzymes and toxic products
• Damage Associated with Adaptive Immunity• Immune complexes: antigen-antibody complexes can
form, settle in kidneys and joints, and activate complement system leading to inflammation
– E.g., acute glomerulonephritis following skin, throat infections of S. pyogenes
• Cross-reactive antibodies: may bind to body’s own tissues, promote autoimmune response
– E.g., acute rheumatic fever following S. pyogenes infection