Host Immune Response To Rhinovirus

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<ul><li>1.Narissara Suratannon, MD.Copyright Wondershare Software </li></ul> <p>2. Introduction50% of children undergo viral respiratory tract infections cause wheezing illnessesRSV, HRV and mixed viral infections are the most common causesRSV : 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 asthmaGern et al.JACI2006;117:72-8James 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 controversialInfections 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 SoftwareCopyright 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 asthmaCopyright Wondershare Software 5. Rhinovirus is an important respiratorypathogen Most common pathogen half of all colds &gt;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.Gerns SlideCopyright Wondershare Software 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.2009:9:73-8Copyright Wondershare Software Pic. from Wigepidia 7. Structures of Rhinovirus Capsid (VP1,2,3) : antigenic diversity Central RNA core (VP4-located inside) Divided on...basis of susceptibility toantiviral agents into HRV-A ,HRV-B , new groups: HRV CReceptors binded to ECs intomajor and minor groups Copyright Wondershare Software 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 rhinovirusRecent observations found that rhinovirus could present in the lower airway and in parenchymaKorppi et al.- Bronchiolitic children (RSV &amp; HRV)Pediatr Infect Dis J 2004;23:995-9Copyright Wondershare Software Kelly and Busse.JACI 2008;122:671-82 9. Clinical evidences for viral induced..Subsequent wheezing (1) Subsequent asthma (2) Copyright Wondershare Software 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 factorsLemanske et Wondershare SoftwareCopyright al.JACI 2005;116:571-7 13. Viral factorsLemanske et Wondershare SoftwareCopyright al.JACI 2005;116:571-7 14. First year wheezing caused by rhinovirus infections were the strongest predictors of subsequent third year wheezingLemanske et Wondershare SoftwareCopyright 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 pathwaysAbul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007,p.23Copyright Wondershare Software 17. Kallal et al. Current Allergy and Asthma Reports 2008, 8:Software Copyright Wondershare 443 450 18. EpitheliumRhinovirus-infected ECs produced cytokines and chemokines for recruitment of inflammatory cells as ahost viral immune responseIL-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 Copyright Wondershare SoftwareKelly 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-cellsCopyright Wondershare Software Kelly and Busse.JACI 2008;122:671-82 20. Kelly Copyright Wondershare Software and Busse.JACI 2008;122:671-82 21. Macrophages Rhinovirus can attach to macrophages but may have limited replicationThis interaction stimulates secretion of IL-1, IL-8, TNF-, IFN- TNF- induction of EC expression of ICAM-1 Allows for leukocytes trafficking Increases the receptor availability on the cells IL-8 : potent chemokine for neutrophilIFN- : limit virus spread by an antiviral state in ECs (strengthen anti-viral responses)Kelly Copyright Wondershare Softwareand Busse.JACI 2008;122:671-82 22. Type 1 IFN ( and ) Induced antiviral stateInhibit viral replicationinduce cells to synthesize enz. thatinterfere viral replicationProtect neighboring cells (paracrineaction)Increases expression of MHC class 1 anddevelopment of TH1 cellsRegulate apoptosis of infected cells Abul K. Abbas et al.,Cellular and Molecular Immunology,6th ed,2007,p.23 Copyright Wondershare Software 23. Neutrophils predominant cell type in both asthma and control subjectsPeripheral blood neutrophils increaseCorrelate with rising of G-CSF and IL-8 levelsNeutrophil elastase : a marker of neutrophil degranulationBenefit or harmful?Clearance of cellular debris via phagocytosisAirway edema , trigger bronchoconstriction and induce mucous gland secretion from goblet cellsKelly 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-, GM-CSF,TNF-Handsel andCopyright Wondershare Software Busse.J Immunol 1998;160: 127984 25. EosinophilsOnly in asthma subjects does the eosinophilic infiltrate persist 6 to 8 weeks after infectionCorrelate with airway hyperresponsivenessReflected by increase ECP, leukotrienesIncreased sputum eosinophils predict loss of asthma controlBarns et al.AJRCCM 2000;161:6472 Copyright Wondershare Software Kelly and Busse.JACI 2008;122:671-82 26. Adaptive Immune ResponseT-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-) CTLs and NKT cellsB- 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 orhas a rapid resolution of the viral illness Gern and Busse. Nat Rev Imm.2002 Software Copyright Wondershare ;2:132-9 28. Risk factors for virus-induced wheezingYoung age (&lt; 6 months)Small lung size (Ped Resp Rev 2004)Exposure to tobacco smokePre-existing airway hyperresponsivenessSeveral genetic factors polymorphisms in genes encoding surfactant proteins, cytokines and chemokines (RSV)HRV polymorphims in IL-10 ??Helminen et al. Pediatr Pulmonol 2008;43:391-5James 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) Copyright Wondershare Software 30. Copyright Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72 31. Copyright Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72 32. Copyright Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72 33. Copyright Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72 34. Copyright Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72 35. Non-viral factorsCopyright Wondershare Software 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 asthmaBut 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 HypothesisLemonske. Ped AI 2002: Wondershare SoftwareCopyright 13 (Suppl. 15): 3843 38. More virulent ??Copyright Wondershare Software 39. What determines the severity of rhinovirus respiratory illnesses?Copyright Wondershare Software 40. Host Factors Critical period of lung developmentAtopyImpaired IFN productionAllergen sensitizationEpithelial defect (barrier defect) : filagrrin Copyright Wondershare Software Holgate JACI 2006;118:587-90 41. James E. Gern.Curr Opin in aller Wondershare SoftwareCopyright and Imm.2009:9:73-8 42. Multivariate analysis (Gender, older siblings, environmental tobacco smoke exposure, breast feeding, daycare attendance, parental asthma)Copyright Wondershare SoftwareKusel et al.JACI 2007;119:1105-10 43. Reijonen et al.Pediatrics Wondershare SoftwareCopyright 2000; 106(6); 1406-10 44. Copyright Wondershare Software 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 Copyright Wondershare Software 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 !! Copyright Wondershare Software James E. Gern.Curr Opin in aller and Imm.2009:9:73-8 47. Copyright Wondershare SoftwareFrom Dr. Gerns slide 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 asthmaJohnston SL, et al. BMJ. 1995;310:12259 Copyright Wondershare Software 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 inflammationacute exacerbation A reduction of IFN-/IL-5 mRNA ratios from sputum of asthma subjects correlate with higher symptom scores TH2 cytokines induce ICAM-1 expression on ECs Copyright Wondershare SoftwareKelly and Busse.JACI 2008;122:671-82 50. Persistence of Rhinovirus to be a predictor of asthma severitySome subjects of asthma show thepresence of rhinovirus without coldsymptoms or exacerbationCorrelated with a greater degree ofairflow obstruction Whether rhinovirus infection can becomepersistent and contribute to asthmaseverity has yet to be established Copyright Wondershare Software Kelly and Busse.JACI 2008;122:671-82 51. SummerizationAsthma is probably a heterogeneous disease3 factors that significantly influence asthma inceptionin the first decade of lifeimmune response aberrations : concept of cytokine dysregulation(TH1/TH2 imbalance)LRTIs in particular RVgeneenvironment interaction (needs to occur at a critical time-period inthe development of the lung)Lemonske. Ped AI 2002: Wondershare SoftwareCopyright 13 (Suppl. 15): 3843 52. Summerization Children who wheeze with HRV may be at particularly high risk for the subsequent development of asthmaThe 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 infectionsCopyright Wondershare Software 53. Summerization New approach to asthma prevention and treatment , try to protect airways against environmental insults rather than focusing on the suppression of inflammationCopyright Wondershare Software 54. Rhinovirus equally infects upper and lower airwayswas 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; 171:64551 Copyright Wondershare Software Kelly and Busse.JACI 2008;122:671-82 </p>

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