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Host Immune Response To Rhinovirus
- 2. 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
- 3. 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
James E. Gern.Curr Opin in aller Wondershare Software
Copyright © and Imm.2009:9:73-8
- 4. 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
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- 5. 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
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- 6. 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
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Pic. from Wigepidia
- 7. 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
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James E. Gern.Curr Opin in aller and Imm.2009:9:73-8 Pic. from Wigepidia
- 8. 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
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Kelly and Busse.JACI 2008;122:671-82
- 9. Clinical evidences for viral induced..
Subsequent wheezing (1)
Subsequent asthma (2)
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- 10. Lemanske et © Wondershare Software
Copyright al.JACI 2005;116:571-7
- 11. Lemanske et © Wondershare Software
Copyright al.JACI 2005;116:571-7
- 12. Non-viral factors
Lemanske et © Wondershare Software
Copyright al.JACI 2005;116:571-7
- 13. Viral factors
Lemanske et © Wondershare Software
Copyright al.JACI 2005;116:571-7
- 14. First year wheezing caused by rhinovirus infections
were the strongest predictors of subsequent third
year wheezing
Lemanske et © Wondershare Software
Copyright al.JACI 2005;116:571-7
- 15. Targets for Infection
Epithelium is the primary
target site of HRV!!
CopyrightBusse.JACI 2008;122:671-82
Kelly and © Wondershare Software
- 16. 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
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- 17. Kallal et al. Current Allergy and Asthma Reports 2008, 8:Software
Copyright © Wondershare 443– 450
- 18. 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
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Kelly and Busse.JACI 2008;122:671-82
- 19. How our body response to HRV?
Innate immune response
Macrophages
Neutrophils
Eosinophils
Adaptive immune response
T-cells
B-cells
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Kelly and Busse.JACI 2008;122:671-82
- 21. 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)
Kelly Copyright © Wondershare Software
and Busse.JACI 2008;122:671-82
- 22. 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
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- 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
Kelly Copyright © Wondershare Software
and Busse.JACI 2008;122:671-82
- 24. 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
- 25. 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
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Kelly and Busse.JACI 2008;122:671-82
- 26. 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
Kelly Copyright © Wondershare Software
and Busse.JACI 2008;122:671-82
- 27. 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
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- 28. 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
James E. Gern.Curr Opin in aller Wondershare Software
Copyright © and Imm.2009:9:73-8
- 29. Clinical evidences for viral induced..
Subsequent wheezing (1)
Subsequent asthma (2)
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- 35. Non-viral factors
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Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
- 36. 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
- 37. 2-Hit Hypothesis
Lemonske. Ped AI 2002: Wondershare Software
Copyright © 13 (Suppl. 15): 38–43
- 39. What determines the severity of
rhinovirus respiratory illnesses?
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- 40. Host Factors
Critical period of lung development
Atopy
Impaired IFN production
Allergen sensitization
Epithelial defect (barrier defect) : filagrrin
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Holgate JACI 2006;118:587-90
- 42. Multivariate analysis (Gender, older siblings, environmental tobacco smoke exposure,
breast feeding, daycare attendance, parental asthma)
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Kusel et al.JACI 2007;119:1105-10
- 45. 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
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James E. Gern.Curr Opin in aller and Imm.2009:9:73-8
- 46. In the case of increased epithelial permeability
(diseased airways)
RV infection is more severe !!
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James E. Gern.Curr Opin in aller and Imm.2009:9:73-8
- 48. 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
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Johnston SL, et al. AJRCCM. 1996;154:654-60
- 49. 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
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Kelly and Busse.JACI 2008;122:671-82
- 50. 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
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Kelly and Busse.JACI 2008;122:671-82
- 51. 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
- 52. 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
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- 53. Summerization
New approach to asthma prevention and
treatment , try to protect airways against
environmental insults rather than focusing
on the suppression of inflammation
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- 54. 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
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Kelly and Busse.JACI 2008;122:671-82