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onsdag 4 juli 2018

Koottua tietoa netistä rinoviruksesta

Kysymyksiä, joihin etsin vastausta: Mikä on  ihmiskehon vaste rinovirukseen ja miten jokin rhinovirus kiertää ihmisen immuunivasteen?
Mitkä ovat tyypillisimmät erot  influensaviruksesta tuleviin oireisiin?
saako rinoviruksiin vasdtustuskykyä?
Onko rokotettta ja onko rokoteen tarvetta?
Mikä on pahin haitta tai vaara  rinoviruksista aikuisille? lapsille?

Materiaalia, jota löysin tänään
 
Challenges in developing a cross-serotype rhinovirus vaccine. Glanville N et al. Curr Opin Virol. (2015) Abstract
 A great burden of disease is attributable to human rhinovirus (HRV) infections which are the major cause of the common cold, exacerbations of both asthma and chronic obstructive pulmonary disease (COPD), and are associated with asthma development.
 Despite this there is currently no vaccine for HRV.
 The first vaccine studies showed some promise in terms of serotype-specific protection against cold symptoms, but antigenic heterogeneity amongst the >150 HRVs has been regarded as a major barrier to effective vaccine development and has resulted in little progress over 50 years.
 Here we review those vaccine studies conducted to date, discuss the difficulties posed by antigenic heterogeneity and describe some recent advances in generating cross-reactive antibodies and T cell responses using peptide immunogens.

(Siis toistaiseksi: olennaista saada PEF arvot tulehduksen jälkeen vähintään samalle tasolle kuin ennen tulehdusta, restriktio ei saa jäädä ja kestää ja pinttyä- ehkä  lyhytaikainen tukea antava  astmaattisia keuhkomuutoksia estävä    ehkä steroidipitoinen inhalaatio hoito olisi astmaprofylaksian kannalta   suositeltava rhonoviruksesta toipumisen jälkeen, ja keuhkorestriktio asteen  kontrolli, palautttaminen ainakin ennen tulehdusta esiintyneisiin keuhkofunktiotasoihin - tässä on sokea piste terapeuttissti ajatellen. Jokainen  paha rhinovirusinfektio voi tuhota joitain funktionaalisia soluja9

 
The potential for a protective vaccine for rhinovirus infections. Williams GR et al. Expert Rev Vaccines. (2016)
Rhinovirus A , B and C, 7 subtypes (A(4), B(1), C (2) . Intraspecies recombinations in A and C.


Kommentti: Rhinovirus on tavallinen ssRNA virus, jolle kehossa on ssRNA sensori RIG-1, adaptori MAVS, joiden kauta  tapahtuu  INF tyyppi1 – antiviraalin vasteen indusoivan  interferonin tuotanto .

  • PubMed artikkeli vuodelta 2017. C-tyypin Rhinoviruksen evaasiostrategiasta.
Rhinovirus tyyppi C: stä enemmän tekstiä , sillä se kiertää jollain tavalla tämän RIG-1 välitteisen tunnistustien. (tunnistus tarkoittaa: Solu huomaa että sisään on tullut vieras RNA- materia. Jos se on lyhyst ssRNA, RIG-1 tunnistaa sen. Sitten on RIG-1 :n kaltaisia reseptoreita muitakin joilla voidaan laajentaa tunnistettavien  RNA virusten  valikoimaa.

 Tutkijat kehittivät RV-C viruksen kliinisistä näyteistä kokopitkän cDNA-kloonin. RV-C ei nostanut IFNbeta mRNA eikä -proteiinitasoja bronkiaaliepiteelin infektoiduissa soluissa. Tämä kyky heikentää IFNbeta aktivaatio havaittiin olevan RV-C- viruksen 3C-proteiinilla, jossa eräs histidiini (40H) oli tärkeässä asemassa. Tämä proteiini 3C aiheutti RIG-1 sensorin hajoamisen kaspaasista riippuvalla tavalla ja virusproteiini pystyi myös pilkkomaan adaptorin  MAVS  kohdasta 148 Q/A, mikä lopullisesti esti IFN-1--signaloinistien. Yhteenvetona RV-C pystyi suorittamaan evaasionsa ylläkuvatulla mekanismilla siten, että infektoitunut solu ei tuottanut IFN-I tyypin interferonia ( eikä siis solu saanut sen avulla normaalia antivirustilaasa aikaan, jolloin olisi yli sata antivirusgeeniä ollut valittavana käynnistettäväksi).

(Käytännön emrkitys:
 Rhinoviruksenkin tyypin diagnosoiminen saattaa olla tärkeä asia. Rokotteesta olisi hyötyä astmaan taipuvaisille, sillä jokainen pahanlaatuinen Rhinovirus vikuuttaa keuhkoa. Ehkä keskittyminen influenssavirustieteeseen on ottanut kaikki reseurssit maailmasta ja rhinovirus on jäänyt sen varjoon- vaikka käytännössä jälkitauti astma  ja pahentunut COPD on hankalampi kuin influenssan usein  olemattomat jälkitaudit  ja lisäksi influenssa jättää jotain immuunivastetta. 

  • Rhinovirus C (RV-C), a newly identified group of human rhinoviruses (RVs), is associated with exacerbation of severe asthma. The type I interferon (IFN) response induced by this virus and the mechanisms of evasion of IFN-mediated innate immunity for RV-C remain unclear. In this study, we constructed a full-length cDNA clone of RV-C (LZ651) from a clinical sample. IFN-β mRNA and protein levels were not elevated in differentiated Human bronchial epithelial (HBE) cells at the air-liquid interface infected with RV-C, except in the early stage of infection. The ability to attenuate IFN-β activation was ascribed to 3Cpro of RV-C, and the 40-His site of 3Cpro played an important role. Furthermore, RIG-I was degraded by 3Cpro in a caspase-dependent manner and 3Cpro cleaved MAVS at 148 Q/A, which inhibited IFN signaling.
  •  Taken together, our results demonstrate the mechanism by which RV-C circumvents the production of type I IFN in infected cells.KEYWORDS: 3C protein; Interferon response; MAVS; RIG-I signaling pathway; Rhinovirus C. PMID: 28576493 DOI: 10.1016/j.bbrc.2017.05.169 [Indexed for MEDLINE]
  • Tietoa vuodelta 2006. Yli 100 rinovirusta tunnetu siihen aikaan. Noin 50 % tavallisista vilustumisista aiheutui jostain rinoviruksesta.
Tak W. Mak, Mary E. Saunders, in The Immune Response, 2006

  • Rhinovirus.

  • Rhinovirus (rhino, “nose”) is a non-enveloped, single-stranded RNA virus and a member of the picornavirus family. Over 100 rhinoviruses are known. About 50% of common colds are caused by some kind of rhinovirus. (About 10% of common colds are due to infection with a different type of virus, such as adenovirus, while the cause in 40% of cases is unknown.)
  • Rhinoviruses thrive in the upper respiratory tract, particularly the nose and throat. The infection is thus characterized by the familiar symptoms of sneezing, excessive nasal secretion (“runny nose”), and congestion (“stuffy nose”). Complications of rhinovirus infection include spreading of the virus from the throat to the sinuses, lower respiratory tract, and middle ear, resulting in sinusitis, laryngitis, and otitis media, respectively.
Löydän valmiin luettelon isäntäkehon vasteesta rhinovirukselle:

  • Host Immune Response To Rhinovirus

  1. 1. Narissara Suratannon, MD. Copyright © Wondershare Software
  2. 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. 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. 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 Copyright © Wondershare Software
  5. 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 Copyright © Wondershare Software
  6. 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 Copyright © Wondershare Software Pic. from Wigepidia
  7. 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 Copyright © Wondershare Software James E. Gern.Curr Opin in aller and Imm.2009:9:73-8 Pic. from Wigepidia
  8. 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 Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82
  9. 9. Clinical evidences for viral induced.. Subsequent wheezing (1) Subsequent asthma (2) Copyright © Wondershare Software
  10. 10. Lemanske et © Wondershare Software Copyright al.JACI 2005;116:571-7
  11. 11. Lemanske et © Wondershare Software Copyright al.JACI 2005;116:571-7
  12. 12. Non-viral factors Lemanske et © Wondershare Software Copyright al.JACI 2005;116:571-7
  13. 13. Viral factors Lemanske et © Wondershare Software Copyright al.JACI 2005;116:571-7
  14. 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. 15. Targets for Infection Epithelium is the primary target site of HRV!! CopyrightBusse.JACI 2008;122:671-82 Kelly and © Wondershare Software
  16. 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 Copyright © Wondershare Software
  17. 17. Kallal et al. Current Allergy and Asthma Reports 2008, 8:Software Copyright © Wondershare 443– 450
  18. 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 Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82
  19. 19. How our body response to HRV? Innate immune response Macrophages Neutrophils Eosinophils Adaptive immune response T-cells B-cells Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82
  20. 20. Kelly Copyright © Wondershare Software and Busse.JACI 2008;122:671-82
  21. 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. 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 Copyright © Wondershare Software
  23. 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. 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 and Copyright © Wondershare Software Busse.J Immunol 1998;160: 1279–84
  25. 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 Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82
  26. 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. 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 Copyright © Wondershare ;2:132-9
  28. 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. 29. Clinical evidences for viral induced.. Subsequent wheezing (1) Subsequent asthma (2) Copyright © Wondershare Software
  30. 30. Copyright © Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
  31. 31. Copyright © Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
  32. 32. Copyright © Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
  33. 33. Copyright © Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
  34. 34. Copyright © Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
  35. 35. Non-viral factors Copyright © Wondershare Software Jackson et al.Am J Respir Crit Care Med 2008;178:667-72
  36. 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. 37. 2-Hit Hypothesis Lemonske. Ped AI 2002: Wondershare Software Copyright © 13 (Suppl. 15): 38–43
  38. 38. More virulent ?? Copyright © Wondershare Software
  39. 39. What determines the severity of rhinovirus respiratory illnesses? Copyright © Wondershare Software
  40. 40. Host Factors Critical period of lung development Atopy Impaired IFN production Allergen sensitization Epithelial defect (barrier defect) : filagrrin Copyright © Wondershare Software Holgate JACI 2006;118:587-90
  41. 41. James E. Gern.Curr Opin in aller Wondershare Software Copyright © and Imm.2009:9:73-8
  42. 42. Multivariate analysis (Gender, older siblings, environmental tobacco smoke exposure, breast feeding, daycare attendance, parental asthma) Copyright © Wondershare Software Kusel et al.JACI 2007;119:1105-10
  43. 43. Reijonen et al.Pediatrics© Wondershare Software Copyright 2000; 106(6); 1406-10
  44. 44. Copyright © Wondershare Software
  45. 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. 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. 47. Copyright © Wondershare Software From Dr. Gern’s slide
  48. 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 Copyright © Wondershare Software Johnston SL, et al. AJRCCM. 1996;154:654-60
  49. 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 Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82
  50. 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 Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82
  51. 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. 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 Copyright © Wondershare Software
  53. 53. Summerization New approach to asthma prevention and treatment , try to protect airways against environmental insults rather than focusing on the suppression of inflammation Copyright © Wondershare Software
  54. 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 Copyright © Wondershare Software Kelly and Busse.JACI 2008;122:671-82


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