Host Immune Response To Rhinovirus

Copyright Copyright ©© Wondershare SoftwareWondershare Software

Narissara Suratannon, MD.


Introduction

50% of children undergo viral

respiratory tract infections

cause wheezing illnesses

RSV, HRV and mixed viral infections

are the most common causes RSV : December to April

(Thai : May to July)

HRV : the rest of the year

30-50% with recurrent virus-induced

wheezing in infancy go on to develop

asthma

James E. Gern.Curr Opin in aller and Imm.2009:9:73-8

Gern et al.JACI2006;117:72-8


Introduction

The question of whether respiratory infections

with viruses can cause asthma is controversial

Infections with RSV : subsequent increased risk of

recurrent wheezing and asthma (Lancet 1999)

Molecular studies have showed the role of HRVs

to acute illness and in exacerbations of asthma

and COPD



Outline

How rhinovirus attack our body?

How our body responses it?

Do viruses increase the risk of developing

subsequent wheezing and asthma?

Role of virus for acute asthma exacerbation

Rhinovirus as a predictor of severity of asthma


Rhinovirus is an important respiratorypathogen

• Most common pathogen– half of all colds– >100 infections in a lifetime- founds everywhere

• URI – including middle ear and sinuses

• LRI– “At risk” populations (infants, elderly, COPD, CF)– Bronchiolitis, bronchitis, pneumonia

• Asthma: exacerbation (and causation?)

Some part from Dr.Gern’s Slide


What is HRV (Human Rhinovirus)?

First recovered in 1950sRhino = nosesmall nonenveloped viruses contain a single-strand RNA Family : PicornaviridaeSpecies : EnterovirusGenus : Rhinovirus

James E. Gern.Curr Opin in aller and Imm.2009:9:73-8 Pic. from Wigepidia


Structures of Rhinovirus

Capsid (VP1,2,3) : antigenic diversity

Central RNA core (VP4-located inside)

Divided on...

basis of susceptibility to antiviral agents into HRV-A ,HRV-B , new groups: HRV “C”

Receptors binded to ECs into major and minor groups

James E. Gern.Curr Opin in aller and Imm.2009:9:73-8 Pic. from Wigepidia


Why Rhinovirus come in our interesting?

Hospitalizd asthmatic patients correlate with

the seasonal peak of rhinovirus

Recent observations found that rhinovirus

could present in the lower airway and in

parenchyma

Korppi et al.- Bronchiolitic children (RSV & HRV)Pediatr Infect Dis J 2004;23:995-9

Kelly and Busse.JACI 2008;122:671-82


Clinical evidences for viral induced..

Subsequent wheezing (1)

Subsequent asthma (2)

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareLemanske et al.JACI 2005;116:571-7



Non-viral factors


Viral factors


First year wheezing caused by rhinovirus infections were the strongest predictors of subsequent third year wheezing


Targets for Infection


Epithelium is the primary target site of HRV!!

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareAbul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007,p.23

host-cell recognition ofdsRNA seems to be animportant pathway forthe initiation of multiplepro-inflammatory andantiviral pathways

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareKallal et al. Current Allergy and Asthma Reports 2008, 8: 443– 450


Epithelium

Rhinovirus-infected ECs produced cytokines and

chemokines for recruitment of inflammatory cells as a host viral immune response

IL-1, IL-6, IL-8, GM-CSF, eotaxins, and RANTES, type I IFN

Target of the virus

Reservoir for the infected virus

The site and source of initial inflammatory response



How our body response to HRV?

Innate immune response Macrophages

Neutrophils

Eosinophils

Adaptive immune responseT-cells

B-cells


Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareKelly and Busse.JACI 2008;122:671-82


Macrophages

Rhinovirus can attach to macrophages but may have limited replication

This interaction stimulates secretion of IL-1, IL-8, TNF-α, IFN- α

TNF-α induction of EC expression of ICAM-1 Allows for leukocytes traffickingIncreases the receptor availability on the cells

IL-8 : potent chemokine for neutrophil

IFN- α : limit virus spread by an antiviral state in ECs (strengthen anti-viral responses)



Type 1 IFN (α and ß)

Induced “antiviral state”

Inhibit viral replication

induce cells to synthesize enz. that interfere viral replication

Protect neighboring cells (paracrineaction)

Increases expression of MHC class 1 and

development of TH1 cells

Regulate apoptosis of infected cells

Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007,p.23


Neutrophils

predominant cell type in both asthma and control subjects

Peripheral blood neutrophils increase

Correlate with rising of G-CSF and IL-8 levels

Neutrophil elastase : a marker of neutrophil degranulation

Benefit or harmful?

Clearance of cellular debris via phagocytosis

Airway edema , trigger bronchoconstriction and induce mucous gland secretion from goblet cells



- Increases in both asthma and control subjects (Holgate et al. 1995)

- EDN , ECP : antiviral properties (Rosenberg. J 2001)

- Expressed ICAM-1 when pretreated with GM-CSF- Eosinophils may act as APC : expressed MHC II , CD 40L

when pretreated with IFN-Ɣ, GM-CSF,TNF-α

Handsel and Busse.J Immunol 1998;160: 1279–84

Eosinophils


Eosinophils

Only in asthma subjects doesthe eosinophilic infiltrate persist6 to 8 weeks after infection

Correlate with airway hyperresponsiveness

Reflected by increase ECP, leukotrienes

Increased sputum eosinophilspredict loss of asthma control

Barns et al.AJRCCM 2000;161:64–72



Adaptive Immune Response

T-cell (intracellular phase)Infected ECs secrete RANTES and IP-10 for promote T-cell chemotaxisExpression of IP-10 required active rhinovirus replicationTH1-cytokines (IL-2, IFN-Ɣ)CTLs and NKT cells

B- cell (extracellular phase)Neutralizing AbsOpsonization



Effective antiviral activity vs Damaging inflammationHighly variable among individuals

Determines whether the patients wheeze or has a rapid resolution of the viral illness

Gern and Busse. Nat Rev Imm.2002 ;2:132-9


Risk factors for virus-induced wheezing

Young age (< 6 months)

Small lung size (Ped Resp Rev 2004)

Exposure to tobacco smoke

Pre-existing airway hyperresponsiveness

Several genetic factors

polymorphisms in genes encoding surfactant proteins, cytokines and chemokines (RSV)

HRV – polymorphims in IL-10 ?? Helminen et al. Pediatr Pulmonol 2008;43:391-5



Clinical evidences for viral induced..

Subsequent wheezing (1)

Subsequent asthma (2)

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareJackson et al.Am J Respir Crit Care Med 2008;178:667-72






Non-viral factors


Clinical studies show relationship between RSV/RV-induced wheezing and subsequent asthma

But the nature of this association has not yet beenclearly defined

Gern and Busse. Nat Rev Imm.2002 ;2:132-9


2-Hit Hypothesis

Lemonske. Ped AI 2002: 13 (Suppl. 15): 38–43


More virulent ??


What determines the severity ofrhinovirus respiratory illnesses?


Host Factors

Critical period of lung development

AtopyImpaired IFN production

Allergen sensitization

Epithelial defect (barrier defect) : filagrrin

Holgate JACI 2006;118:587-90

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareJames E. Gern.Curr Opin in aller and Imm.2009:9:73-8

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareKusel et al.JACI 2007;119:1105-10

Multivariate analysis (Gender, older siblings, environmental tobacco smoke exposure,

breast feeding, daycare attendance, parental asthma)

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareReijonen et al.Pediatrics 2000; 106(6); 1406-10



Cofactors that may contribute to asthma

Air pollution: personal NO2 exposure

– Chauhan A, Lancet 361:1939, 2003

Tobacco smoke, non-use of ICS

– Venarske, JID 193:1536, 2006


Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareJames E. Gern.Curr Opin in aller and Imm.2009:9:73-8

In the case of increased epithelial permeability(diseased airways)

RV infection is more severe !!

Copyright Copyright ©© Wondershare SoftwareWondershare SoftwareFrom Dr. Gern’s slide


Asthma and Viral Respiratory Infections

Most asthma exacerbations

(50-85%) are related to viral

infection

Any respiratory pathogen (eg,

RSV, parainfluenza) can

precipitate attacks, but RV

are the most common

Seasonal VRIs correlate with

hospital admissions for

asthma

Johnston SL, et al. BMJ. 1995;310:1225–9Johnston SL, et al. AJRCCM. 1996;154:654-60


Why are some patients with asthma more susceptible to rhinovirus LRI?

Not all asthmatic patients have an exacerbation with a cold Some patients - impaired anti-viral response Enhanced of rhinovirus replication Causing greater airway inflammation acute exacerbationA reduction of IFN-Ɣ/IL-5 mRNA ratios from sputum of asthma subjects correlate with higher symptom scores TH2 cytokines induce ICAM-1 expression on ECs



Persistence of Rhinovirus to be a predictor of asthma severity

Some subjects of asthma show the presence of rhinovirus without cold symptoms or exacerbation

Correlated with a greater degree of airflow obstruction

Whether rhinovirus infection can become persistent and contribute to asthma severity has yet to be established



Asthma is probably a heterogeneous disease

3 factors that significantly influence asthma inception

in the first decade of lifeimmune response aberrations : concept of cytokine dysregulation(TH1/TH2 imbalance)

LRTIs in particular RV

gene–environment interaction (needs to occur at a critical time-period inthe development of the lung)

Lemonske. Ped AI 2002: 13 (Suppl. 15): 38–43

Summerization


SummerizationChildren who wheeze with HRV may be at particularly high risk for the subsequent development of asthma

The relationship between respiratory infections and induction of asthma is complex :

interactions between host factors such as age and stage of development of innate and adaptive immune mechanisms at the time of infection (immune maturation)

pathogenic factors such as the number and severity of infections


New approach to asthma prevention and treatment , try to protect airways against environmental insults rather than focusing on the suppression of inflammation

Summerization


Rhinovirus equally infects upper and lower airways

was previously thought to infect primarily upper airway epithelium (Optimal replication occurs between 33 and 35 °C)

Has been detected in lower airway ECs and secretions after experimental inoculation with rhinovirus (BT 37 °C)

Mosser et al. Am J Respir Crit Care Med 2005; 171:645–51


Host Immune Response To Rhinovirus

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