Host Immune Response To Rhinovirus

Narissara Suratannon, MD.
Copyright © Wondershare Software

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

Gern et al.JACI2006;117:72-8

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

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 respiratory
pathogen
• 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 1950s
Rhino = nose
small nonenveloped viruses
contain a single-strand RNA
Family : Picornaviridae
Species : Enterovirus
Genus : 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)


Lemanske et © Wondershare Software
Copyright 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!!

CopyrightBusse.JACI 2008;122:671-82
Kelly and © Wondershare Software

host-cell recognition of
dsRNA seems to be an
important pathway for
the initiation of multiple
pro-inflammatory and
antiviral pathways

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

Kallal et al. Current Allergy and Asthma Reports 2008, 8:Software
Copyright © Wondershare 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 response
T-cells
B-cells


Kelly Copyright © Wondershare Software
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 trafficking
Increases 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 (paracrine
action)
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


Eosinophils
- 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 andCopyright © Wondershare Software
Busse.J Immunol 1998;160: 1279–84

Eosinophils

Only in asthma subjects does
the eosinophilic infiltrate persist
6 to 8 weeks after infection

Correlate with airway
hyperresponsiveness

Reflected by increase ECP,
leukotrienes

Increased sputum eosinophils
predict 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 chemotaxis
Expression of IP-10 required active
rhinovirus replication
TH1-cytokines (IL-2, IFN-Ɣ)
CTLs and NKT cells

B- cell (extracellular phase)
Neutralizing Abs
Opsonization


Effective antiviral activity vs Damaging inflammation
Highly variable among individuals
Determines whether the patients wheeze or
has a rapid resolution of the viral illness

Gern and Busse. Nat Rev Imm.2002 Software
Copyright © Wondershare ;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


Jackson et al.Am J Respir Crit Care Med 2008;178:667-72

Non-viral factors

Jackson et al.Am J Respir Crit Care Med 2008;178:667-72

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

But the nature of this association has not yet been
clearly defined

Gern and Busse. Nat Rev Imm.2002 Software
Copyright © Wondershare ;2:132-9

2-Hit Hypothesis

Lemonske. Ped AI 2002: Wondershare Software
Copyright © 13 (Suppl. 15): 38–43

More virulent ??


What determines the severity of
rhinovirus respiratory illnesses?


Host Factors

Critical period of lung development

Atopy
Impaired IFN production
Allergen sensitization
Epithelial defect (barrier defect) : filagrrin

Holgate JACI 2006;118:587-90

Multivariate analysis (Gender, older siblings, environmental tobacco smoke exposure,
breast feeding, daycare attendance, parental asthma)
Kusel et al.JACI 2007;119:1105-10

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


In the case of increased epithelial permeability
(diseased airways)
RV infection is more severe !!


From 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;310:1225–9
Johnston 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 exacerbation
A 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


Summerization

Asthma is probably a heterogeneous disease

3 factors that significantly influence asthma inception
in the first decade of life
immune response aberrations : concept of cytokine dysregulation
(TH1/TH2 imbalance)
LRTIs in particular RV
gene–environment interaction (needs to occur at a critical time-period in
the development of the lung)

Lemonske. Ped AI 2002: Wondershare Software
Copyright © 13 (Suppl. 15): 38–43

Summerization
Children 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


Summerization

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


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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