Fertőzések immunológiája 9. Influenza november 21. Bajtay Zsuzsa

Átírás

1 Fertőzések immunológiája 9. Influenza november 21. Bajtay Zsuzsa

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3 17.2. ábra Az immunválasz kialakulása és lezajlása patogén hatására

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5 17.3. ábra A sejtközötti térben és a sejten belül élő és szaporodó kórokozók ellen kialakuló védekezési mechanizmusok

6 Zoonózis

7 17.5. ábra T-limfociták polarizációja

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9 17.7. ábra A vírusfertőzés alatt lezajló veleszületett és adaptív immunreakciók időkinetikája

10 17.6. ábra A vírusfertőzés gátlása és a fertőzött sejtek eliminálása a veleszületett és az adaptív immunválasz által IL-12

11 IFN-induced antiviral proteins and their function Protein MxA (Myxovirus resistance gene A) Function Inhibits viral replication by interfering with the viral ribonucleoprotein structure PKR (Protein kinase R) Limits viral replication by blocking general translation OAS (2' 5'oligoadenylate synthetase) Stops viral replication by means of activating RNAseL which results in degradation of viral and cellular RNA and eventually apoptosis of the virus infected cell ISG15 (IFN-stimulated gene 15) Regulates a number of IFN-stimulated proteins Viperin Inhibits viral release by interfering with viral budding Tetherin IFITMs Inhibits formation of influenza virus particles Restrict viral entry Van de Sandt, Viruses, 2012

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14 17.8. ábra Az influenzavírus szerkezete A-, B-, C-, D variánsok, nukleoproteinek és mátrix fehérjék alapján különíthetők el RNS-polinerázok PA, PB1, PB2 M1 A virális glikoproteinről és a gazdasejt membránjának glikoproteinjéről hasítja le a sziálsavat; elősegíti a vírus leválását a gazdasejtről RNA polimerase: B1, PB2, PA, NP NS1 (nonstructural protein) virulence factor NEP - nuclear export protein gazdasejt glikoprotein-/glikolipidsziálsav-csoportjaihoz kötődik elősegíti az endocitózist, majd a membránfúziót az endoszóma membránnal -RNS vírusgenom a citoplazmába jut

15 Influenza virus proteins. Abbreviation Protein Location Significance in IAV-S Vaccines HA Hemagglutinin Envelope NA Neuraminidase Envelope M2 Matrix 2 Envelope M1 Matrix 1 Internal NP Nucleoprotein Internal NS1 Nonstructural protein 1 Nonstructural NS2/ NEP Nonstructural protein 2/Nuclear export protein PA Polymerase acidic protein Internal PB1 Polymerase basic protein 1 Internal PB1-F2 Nonstructural or internal Internal PB2 Polymerase basic protein 2 Internal Subtype of HA in inactivated virus vaccine must match challenge virus. Vaccines with more closely related HA are more likely to be protective. NA content in vaccines is not standardized, but studies indicate a role in protection [17,18,19,20]. Experimental vaccines were directed against highly conserved M2 [21,22]. Gene deletion in NS1confers attenuation in a candidate vaccine [23,24]. Mutations in PB1 and PB2 confer attenuation in a candidate vaccine [25]. Mutations in PB1 and PB2 confer attenuation in a candidate vaccine [25].

16 Influenza virus infection cycle Influenza viruses are divided into subtypes; A, B, C and D, based on different nucleoand matrix-protein. Human influenza A and B viruses cause seasonal epidemics of disease almost every winter. The emergence of a new and very different influenza A virus to infect people can cause an influenza pandemic. Flu viruses are spread mainly by droplets and initiate infection in the upper respiratory tract and made people with flu cough, sneeze and fever. An influenza pandemic has always been a great global infectious-disease threat. There have been 10 pandemics of influenza A in the past 300 years. The pandemic of 1918 and 1919 killed 50 million to 100 million people. Lambert, NEJM,2010 Matthew, Vaccines, 2015

17 Influenza virus infection cycle Infection begins with the binding of hemagglutinin (HA) proteins to receptor molecules on the cell surface. New viral particles containing eight RNA segments bud off from the cell membrane. Neuraminidase (NA) protein cleaves the bonds between HA and sialic acid molecules, allowing new virus to disperse. Lambert, NEJM,2010

18 ábra Az influenzavírus szaporodásának és fertőzőképességének gátlása

19 Influenza fertőzés Felső légúti fertőzés Receptorhoz kötődés Membránfúzió, unpacking Vírusfehérjék termelése - Budding A vírus az epitélsejtek sziálsav-receptoraihoz kötődik, endocitózissal kerül a sejtbe A savas közeg segíti a vírus és az endoszóma membrán fúzióját Az M2 csatornán át beáramló H-ionok hatására a vírus genom a citoplazmába kerül A citopatikus vírus néhány napig szaporodik a tüdő epitélsejtjeiben Szövetkárosodás, gyulladás alakul ki,ami kedvez a koinfekcióknak Adaptív védelem: Tc és IgA + Bm

20 17.1. ábra Az influenza A vírus járványt, ill. pandémiát okozó altípusainak megjelenése az 1900-as évektől H1N1 H1N1 caused spanyol "Spanish nátha Flu" H1N109 and the disznó-ember 2009 swine flu outbreak (novel H1N1) H2N2 H2N2 caused ázsiai vírus "Asian Flu" H3N2 H3N2 caused hongkongi "Hong virus Kong Flu

21 Influenza pandémia Krammer, Nat Rev Dis Prim, 2018

22 Influenza pandemics The WHO estimates that annual epidemics of influenza result in ~1 billion infections, 3 5 million cases of severe illness and 300, ,000 deaths. pandemic type period mortality mortality rate Spanish flu H1N million 2% Asian flu H2N million 0.13% Hongkong flu H3N million <0.1% Russian flu H1N na na 2009 flu H1N ezer 0.03% global more than half in young adults 20 to 40 years old o originated from mutation in wild ducks combining with a pre-existing human strain descended from H2N2 by antigenic shift, in which genes from multiple subtypes reassorted to form a new virus a "benign" pandemic, primarily affecting people born after Older generation had protective immunity resulting from prior experience with H1N1 strains. first identified in April reassortment of four known strains; one endemic in humans, one in birds, and two in swine.rapid spread due to a general lack of antibody-mediated immunity in the human population

23 Influenza-A altípusai - Ember és állat is fertőződik - Vírus antigének folyamatosan változnak: H (18) és N (11) - Madarak (vad-, baromfi) és sertések a vírustörzsek rezervoárjai - Ellananyag felismerés nem hatékony - Évente új vakcina szükséges Gnicholson, Lancet, 2003

24 Az influenza-a vírus terjedése Krammer,2018,Nat Rev Dis Primers

25 Állati influenzavírus direkt vagy indirekt úton okozhat emberi megbetegedést

26 Spanyol nátha Ázsiai inf Hongkongi inf Új inf

27 Spanish Asian Hongkong New Flu pandemics caused by host switch events About 52 key genetic changes distinguish avian influenza strains from human strains: PB2: RNA polymerase, at position 627 avian influenza viruses had a Glu, human influenza viruses had a lysine. HA: Avian bind alpha 2 3 sialic acid receptors, human bind alpha 2 6 sialic acid receptors strain, which is the only pandemic influenza virus that could be entirely derived from avian strains. Of the 52 species-associated positions, 16 have residues typical for human strains; the others remained as avian signatures. The 1918 pandemic virus is more closely related to the avian influenza A virus than are other human influenza viruses.

28 17.9. ábra Influenzavírus felszíni antigének változásának mechanizmusa az antigén-drift és az antigén-shift Antigéndrift - H és N pontmutációk - Neutralizáló ellenanyag nem ismeri fel - Epidémia alakul ki Antigénshift - Két különböző vírus fertőzi meg ugyanazt a sejtet - ssrns csere új vírustörzs jön létre - Ellenanyagok nem ismerik fel - Pandémia alakul ki

29 Influenza and antigenic shift Antigenic shift can arise when genes encoding at least the haemagglutinin surface glycoprotein are introduced into people, by direct transmission of an avian virus from birds, as occurred with H5N1 virus, or after genetic reassortment in pigs, which support the growth of both avian and human viruses. Gnicholson, Lancet, 2003

30 Random mutations in HA and NA genes of an influenza-a virus in swine strain may cause significant changes in antigenic properties. A swine herd with population immunity to Influenza-A virus in swine has neutralizing antibodies specific to a strain that was previously encountered through infection or vaccination. Antigenic drift produces a new variant strain that pre-existing antibodies in the herd are unable to neutralize, the pigs become susceptible to reinfection. Matthew, Vaccines, 2015

31 Influenzavírus antigén-drift és antigén-shift Epidémiák - antigén drift: elsősorban HA mutációk szezonális fertőzés Pandémia - antigenic shift: új vírus altípus kialakulása - hatékony nab hiányában gyors terjedés emberről emberre van de Sandt, Viruses, 2012

32 A. Fajok közötti terjedés B. Koinfekció Sertésben: sh3n2 + huh1n1 új H1N2 nincs hatékony ellenanyag válasz Sem sertésben, sem emberben Matthew, Vaccines, 2015

33 Host switch events often occur through reassortment Asian

34 Influenza A/HongKong/97 (H5N1), 2006 Highly pathogenic H5N1 avian influenza kills 50% of humans that catch it. The Avian Flu virus H5N1 has the potential to mutate into a pandemic strain. H5N1 virus-induced cytokine storm can led to the acute respiratory distress syndrome: ARDS Osterholm,NEJM,2005

35 Influenza tesztek Diagnostic assay Description Advantages Disadvantages Virus culture Virus detected by the appearance of cytopathic effect, HA assay or direct fluorescence antibody staining High specificity ( >95%) 237 Enables characterization of novel viruses Enables surveillance of antiviral sensitivity and antigenic drift Slow ( >3 days) Requires specialized skills and equipment Lower sensitivity than RT-PCR RT-PCR Primers to conserved genes can be used in combination with those for HA High specificity ( >99%) 238 High sensitivity ( >99%) 238 Can be multiplexed 238 Can be automated in relatively high throughput Moderately fast (hours) Can be used to simultaneously type and subtype viruses 239 Expensive More prone to false positive results (by nucleic acid contamination) than virus culture 238 Rapid antigen test Immunoassay detection of the presence of viral antigen in the sample Fast (15 min) Low cost Point of care Can detect both influenza A and influenza B Low sensitivity (70 50%)240,241 Prone to false negative results241 (96% negative predictive value) Cannot provide subtype information Rapid molecular assay Based on isothermal nucleic acid amplification; requires simple heat source and fluorescence detection Fast (15 min) High specificity ( >99%) 240 Good sensitivity (66 100%) 240 Point of care Expensive

36 Influenza vakcina (HA, NA, M2, NP antigének + adjuváns) Krammer, Nat Rev Dis Primers, 2018

37 All of the licensed, conventional Fluvaccines contain inactivated (killed) virus. Each strain of virus is cultivated in eggs or cell culture and inactivated with chemical agents, such as formaldehyde. Inactivated viruses of multiple strains are blended and formulated with an adjuvant. Regulatory approval of an inactivated virus vaccine requires successful demonstration of safety and efficacy. Efficacy is determined by experimental Albanesi,Clin.Immunol. challenge of seronegative animals.

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39 5 key facts about Influenza virus evolution Johnson, Plos Pathog, 2017