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Mediação Imunológica da patogenicidade do vírus chikungunya
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  of December 6, 2017.This information is current as Pathogenesis of Chikungunya VirusImmune-Mediated Protection and Julie M. Fox and Michael S. Diamondhttp://www.jimmunol.org/content/197/11/4210doi: 10.4049/jimmunol.16014262016; 197:4210-4218; ;  J Immunol average *   4 weeks from acceptance to publication Speedy Publication! ã Every submission reviewed by practicing scientists No Triage! ã from submission to initial decision Rapid Reviews! 30 days* ã ? The JI  Why References http://www.jimmunol.org/content/197/11/4210.full#ref-list-1, 20 of which you can access for f ree at: cites 84 articles This article Subscription http://jimmunol.org/subscription is online at: The Journal of Immunology Information about subscribing to  Permissions http://www.aai.org/About/Publications/JI/copyright.htmlSubmit copyright permission requests at: Email Alerts http://jimmunol.org/alertsReceive free email-alerts when new articles cite this article. Sign up at: Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunologists, Inc. All rights reserved.Copyright © 2016 by The American Association of 1451 Rockville Pike, Suite 650, Rockville, MD 20852The American Association of Immunologists, Inc., is published twice each month by The Journal of Immunology   b  y g u e  s  t   onD e  c  e m b  e r  6  ,2  0 1  7 h  t   t   p :  /   /   w w w . j  i  mm un ol   . or  g /  D o wnl   o a  d  e  d f  r  om  b  y g u e  s  t   onD e  c  e m b  e r  6  ,2  0 1  7 h  t   t   p :  /   /   w w w . j  i  mm un ol   . or  g /  D o wnl   o a  d  e  d f  r  om   Immune-Mediated Protection and Pathogenesis of Chikungunya Virus  Julie M. Fox* and Michael S. Diamond* , † , ‡ , x Chikungunya virus (CHIKV) is a re-emerging alphavi-rus that causes debilitating acute and chronic arthritis.InfectionbyCHIKVinducesa robustimmuneresponsethat is characterized by production of type I IFNs, re-cruitment of innate and adaptive immune cells, and de- velopment of neutralizing Abs. Despite this response,chronic arthritis can develop in some individuals, whichmay be due to a failure to eliminate viral RNA and Ag and/or persistent immune responses that cause chronic  joint inflammation. In this review, based primarily onadvancesfromrecentstudiesinmice,wediscusstheinnateandadaptiveimmunefactorsthatcontrolCHIKVdissem-inationandclearanceorcontributetopathogenesis.  The  Journal of Immunology  , 2016, 197: 4210–4218. C hikungunyavirus(CHIKV)isare-emergingmosquito-borne enveloped alphavirus in the  Togaviridae   family.CHIKV has a single-stranded positive sense RNA ge-nome that encodes four nonstructural proteins (nsP1, nsP2,nsP3, and nsP4) and five structural proteins (capsid, E3, E2, 6K,and E1) from two open reading frames. CHIKV was first iso-lated in Tanzania in 1952 and has caused explosive outbreaksthroughout Africa, India, Southeast Asia, and Polynesia (1, 2).CHIKV emerged in the Caribbean in 2013 and has spreadthroughout Central and South America, with autochthonoustransmission reported in Florida (3). The outbreak in the Americas has resulted in more than 1.8 million suspected cases(4). Historically, CHIKV was transmitted principally by   Aedes aegypti   mosquitoes, but in 2006 the virus acquired a singlemutation (A226V) in the E1 protein that facilitated enhancedreplication and transmission in  Aedes albopictus   mosquitoes,which expanded its geographical range (5). There are threegenotypes of CHIKV that are highly conserved, with 95.2–97% identity at the amino acid level: the East/Central/South African and Asian genotypes are more closely related than themore distantly related West African genotype (6, 7). Following a short incubation period after mosquito bite, CHIKV infec-tion in humans can cause fever, rash, malaise, myalgia, anddebilitating polyarthralgia and polyarthritis that usually lasts for1–4 wk (8). Depending on the study, ~10–60% of affectedindividuals develop chronic arthritis that lasts for months toyears following infection (9–12). CHIKV infection rarely re-sults in mortality, although it has been reported in the elderly,infants, and immunocompromised (13–15). Currently no ap-proved vaccines or therapeutics are available to prevent CHIKV infection or treat disease at the acute or chronic stages.Over the past decade, the immunobiology of CHIKV in-fection and disease has been studied intensively in laboratory animal models, primarily in mice but also in some nonhumanprimate species. Experimental infection of different strains of immunocompetentmice (e.g.,C57BL/6,CD1,IRC)results inan acute disease similar to that in humans, including highviremia, viral replication in joint and muscle tissues, synovitis,and myositis (16–19). After inoculation of CHIKV into theskin, the virus likely replicates in fibroblasts, mesenchymalcells, and osteoblasts (20, 21). CHIKV induces a local cyto-kine and chemokine response that recruits NK cells, mac-rophages, inflammatory monocytes, and CD4 + and CD8 + T cells (16, 17, 20). Damage from viral replication and im-mune cell infiltration results in local edema, extensive myo-fiber degeneration, and injury and loss of mesenchymal cellslining the synovium and periosteum (22). Moreover, CHIKV infection of osteoblasts elevates the ratio of receptor activatorof NF- k B ligand to osteoprotegerin in the ankle and knee,which increases osteoclast generation and can promote boneloss (23). In mice, CHIKV infection causes a biphasic patternof swelling in the ipsilateral inoculated foot, with a small peak between 2 and 3 d postinfection (dpi) and a second, largerpeak at 6–7 dpi (17, 24). The first peak is most likely due toextensive viral replication in the foot, which results in celldeath, cytokine production, and tissue edema. The secondpeak occurs as infectious virus is cleared from the blood andwithin tissues, and is associated with the influx of inflam-matory cells into joints of the foot and surrounding tissues,causing more edema, myositis, and synovitis. This histologicalobservation suggests that the second, more prominent peak isdriven by immune-mediated response and damage. Although *Department of Medicine, Washington University School of Medicine, St. Louis, MO63110;  † Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;  ‡ Department of Molecular Microbiology, WashingtonUniversity School of Medicine, St. Louis, MO 63110; and  x Center for Human Immu-nology and Immunotherapy Programs, Washington University School of Medicine,St. Louis, MO 63110Received for publication August 16, 2016. Accepted for publication September 13,2016.This work was supported by National Institutes of Health Grants R01 AI073755, R01 AI104972, and R01 AI114816. J.M.F. was supported by National Institutes of HealthGrant T32 AI007172. Address correspondence and reprint requests to Dr. Michael S. Diamond, WashingtonUniversity School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mailaddress: diamond@wusm.wustl.edu Abbreviations used in this article: CHIKV, Chikungunya virus; DKO, double knockout;dpi, day postinfection; ISG, IFN-stimulated gene; PKR, protein kinase R; PRR, patternrecognition receptor; Treg, regulatory T cell; WT, wild-type. Copyright  2016byTheAmericanAssociationofImmunologists,Inc.0022-1767/16/$30.00www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601426  Journal   of  Te Immunology  Brief Reviews   b  y g u e  s  t   onD e  c  e m b  e r  6  ,2  0 1  7 h  t   t   p :  /   /   w w w . j  i  mm un ol   . or  g /  D o wnl   o a  d  e  d f  r  om   infectious virus is cleared by 7 dpi, CHIKV RNA can bedetected in joints (e.g., feet and ankles, and wrists) for  $ 4 wk postinfection. Mice infected with a CHIKV strain encoding firefly luciferase showed bioluminescent signal in the foot at 45 dpi (25).Using mice lacking specific factors of innate and adaptive im-munity, researchers have identified some of the key immunecorrelates of CHIKV disease pathogenesis and protection (Fig. 1,Table I) and have related them to observations from human co-hort studies. Innate immune response to CHIKV infection  Recognition of CHIKV RNA and induction of antiviral pathways. The mammalian host response to CHIKV infection startslocally in the skin at the site of inoculation and also occurs inthe underlying muscle and joint tissues (18, 26). The CHIKV RNA genome can trigger host pattern recognition receptors(PRRs), including endosomal TLRs (TLR3 and TLR7) andcytoplasmic RIG-I–like (RIG-I and MDA5) receptors, whichactivate downstream adaptor molecules (e.g., TRIF, MyD88,and MAVS) to induce nuclear translocation of IRF3- and type IIFN–dependent antiviral responses (27–29). Although thisscheme generally is accepted for many viruses, reports conflictregarding the necessity of individual PRRs in the antiviralresponse against CHIKV in mice. For example, one groupshowed a protective effect of TLR3, as  Tlr3  2 /   2 mice sustainedincreased viremia and tissue viral burden with augmented footswelling and edema, infiltration of CD11b + F4/80 + macrophagesand CD11b + Ly6G + neutrophils, and reduced numbers of CD4 + T cells (30). Depletion of the remaining CD4 + T cells inthe  Tlr3  2 /   2 mice diminished foot swelling but also reducedthe number of infiltrating neutrophils; the authors suggestedthat the increased recruitment of neutrophils in the CHIKV-infected  Tlr3  2 /   2 mice promotes the observed enhancedmusculoskeletal inflammation (30). In this study, TLR3stimulation in hematopoietic cells controlled CHIKV viremia,whereas TLR3 signaling in nonhematopoietic cells resulted inreduced clinical disease. Remarkably, a second group observedno virological differences between  Tlr3  2 /   2 and wild-type (WT)mice (20). Potential reasons for the disparity in viral infectionphenotype may be related to the age of mice inoculated and themethod of virus detection. The first group used 3-wk-old miceand analyzed viral burden by quantitative RT-PCR (30). Thesecond group did not disclose the age of mice used anddetermined viral burden by 50% tissue culture infective doseanalysis (20). An antiviral role for TLR3 is supported by studies FIGURE 1.  Overview of CHIKV and immune-mediated pathogenesis in mice. CHIKV infection of the footpad results in edema and inflammation from viralinfection, cell death, cytokine production, and immune cell infiltration. Foot swelling is biphasic, with the first ( 1 ) peak occurring 2–3 dpi followed by a second ( 2 )peak at 6–7 dpi. ( 1 ) CHIKV infects fibroblasts (orange cells), mesenchymal cells, and osteoblasts. In this figure, infection is indicated with viral RNA presentinside a cell with a plasma membrane colored orange. PRRs are triggered during cellular infection, resulting in activation of transcription factors, ultimately producing type I IFNs. Type I IFN and the ISG response are necessary to prevent severe disease. In addition, PRR and IFN signaling induces secretion of proinflammatory cytokines and chemokines, which recruit innate and adaptive immune cells to the site of infection, driving inflammation. Depletion of NK cellsreduces foot swelling, suggesting a pathogenic role. Macrophages (M F ) and inflammatory monocytes have dual protective and pathogenic roles in CHIKV arthritis. Depletion of macrophages reduces swelling but also can result in a neutrophil-mediated immunopathogenesis. Osteoblasts can be infected by CHIKV,which promotes osteoclastogenesis and bone reabsorption.  gd + T cells prevent monocyte recruitment and joint inflammation. ( 2 ) CHIKV infection induces a neutralizing Ab (NAb) response that eliminates infectious virus from circulation and tissues. Effector CD4 + T cells are recruited to musculoskeletal tissues andsecrete IFN- g . Depletion of CD4 + T cells results in reduced joint swelling. Enhancement of the Foxp3 + CD4 + Treg response results in reduced joint swelling,cytokine production, and effector CD4 + T cell activation. Surprisingly, CD8 + T cells do not seem to function in acute pathogenesis or viral clearance, at least inmice. CHIKV RNA and Ag persist in joint tissues for extended periods and may serve as pathogen-associated molecular patterns for chronic immune activationand inflammation. Macrophages and monocytes are suggested to be a reservoir for chronic infection. The Journal of Immunology 4211   b  y g u e  s  t   onD e  c  e m b  e r  6  ,2  0 1  7 h  t   t   p :  /   /   w w w . j  i  mm un ol   . or  g /  D o wnl   o a  d  e  d f  r  om   Table I. Clinical, immune, and viral phenotypes after CHIKV infection in mice Immune Function andMouse Strain (Age) a  Virus Strain (Genotype) Clinical/Swelling/Pathology Virological and Immune Characterization Refs.  WTNeonatal (9–12 d) 06.21 (ECSA); CHIKV-21(ECSA)40–60% Survival V: detectable in muscle, serum, brain,liver, lung (32, 34, 42)I: robust cytokine and IFN responseby 24 h pi Young (3–4 wk) SL15649 (ECSA); AF15561(Asian)Inoculated foot swelling;edema, tenosynovitis,tendinitisV: detectable in foot, serum, muscle,liver, brain; persistent RNA in jointsand spleen(16, 18, 63)I: innate and adaptive cell infiltrations;IgM and IgG produced Adult (6–12 wk) Asian isolate; LR2006-OPY1(ECSA)Inoculated foot swelling;edema, arthritis,tenosynovitis(ECSA  .  Asian)V: detectable in serum, foot, muscle,spleen, LN, liver; persistent RNA in joints(17, 80)I: proinflammatory cytokineinduction; innate and adaptive cellinfiltration; IgG2c dominant Antiviral pathways Tlr3  2 /   2 (young) SGPO11 (ECSA)  ↑  Foot swelling V:  ↑  viremia and tissue titers (30)I:  ↑  infiltration of macrophages,neutrophils;  ↓  CD4 + T cells;  ↓  IgGneutralization Tlr3  2 /   2 CHIKV-21 ND V: no  D  in titers (1–3 dpi) (20) Trif   2 /   2 (adult) LR2006-OPY1  ↑  Foot swelling V:  ↑  viremia (31)I:  ↓  type I IFNs Rig-I  2 /   2 (ICR/129/C57BL/6) CHIKV-21 ND V: no  D  in tissue, slight increase inviremia (20) Mda5  2 /   2 (ICR/129/C57BL/6) CHIKV-21 ND V: no  D  in viremia or tissues(72 h pi)(20) Mavs  2 /   2 (adult) CHIKV-21; LR2006-OPY1  ↑  Foot swelling V:  ↑  viremia (20, 31)I: no type I IFNs Myd88  2 /   2 (adult) CHIKV-21; LR2006-OPY1 No  D  in foot swelling V:  ↑  viremia and tissue titers (20, 31)I:  ↓  type I IFNs Irf3  2 /   2 Irf7  2 /   2 (adult) LR2006-OPY1; CHIKV-21  ↑  Foot swelling; 100% lethal V:  ↑  tissue burden (31, 32)I:  ↑  IL-6, TNF- a , IFN- g ; no type IIFNs; shock syndrome Irf3  2 /   2 (adult) LR2006-OPY1; CHIKV-21  ↑  Foot swelling V: no  D  in foot titer or viremia (31, 32)I: no  D  type I IFNs or no type I IFNs Irf7  2 /   2 (adult) LR2006-OPY1; CHIKV-21  ↑  Foot swelling V:  ↑  viremia; no  D  in foot titer I; notype I IFNs(31, 32) Stat1 2 /   2 (129/Sv) CHIKV-21, LR2006-OPY1,37997 (WA) ↑  Foot swelling in ips. andcontra. (LR); 100% lethalV:  ↑  tissue titers (20, 35) Ifnar1 2 /   2 (C57BL6, 129/Sv)(adult)CHIKV-21 100% Lethal V:  ↑  viremia and tissue titers (32, 34, 35) Rsad2  2 /   2 (young) SGP 011 (Asian)  ↑  Foot swelling V: ↑  viremia late;  ↑  foot titer (38)I:  ↑  F4/80 + macrophages Gadd34  2 /   2 (neonatal) CHIKV-21 100% lethal V:  ↑  tissue titers (36)I:  ↓  type I IFNs Ifitm3  2 /   2 (young) LR2006-OPY1  ↑  Foot swelling V:  ↑  tissue titers (39)I:  ↑  macrophage infection Bst2  2 /   2 181/25 (Asian) No swelling (attenuatedvirus)V:  ↑  viremia and tissue titers (40)I:  ↓  type I IFNs and IFN- g Isg15  2 /   2 (neonatal) 06.21 100% Lethal V: no  D  (42)I:  ↑  cytokines; shock syndromeInnate cellular responsesMacrophage depletion(clodronate) (adult)LR2006-OPY1  ↓  Foot swelling V:  ↑  viremia (late) (17) Ccr2  2 /   2 (adult) LR2006-OPY1  ↑  Foot swelling V: no  D  (53)I:  ↑  neutrophils and eosinophils;  ↑ inflammatory cytokinesNK cell depletion (young) LR2006-OPY1;CNR20235 (Asian) ↓  Foot swelling early;no  D  (Asian)V: ND (59) gd TCR  2 / 2 (young) SL15649  ↑  Foot swelling;  ↓  weightgainV: no  D  in viral burden or clearance (61)I:  ↑  inflammatory and regulatory monocytes;  ↑  cytokines Adaptive cellular responses Rag1 2 /   2 or Rag2  2 /   2 (adult;young)LR2006-OPY1; SL15649,SGP11, AF15561 ↓  Foot swelling; chronicsynovitis, tendinitisV:  ↑  viremia (acute) and persistentvirus in periphery and serum(18, 25,62, 63)I:  ↓  cellular infiltrates;  ↑  in neutrophils(chronic) Cd8  2 /   2 or CD8 depletion(adult)SGP11; LR2006-OPY1-Fluc No  D  V: no  D  (25)( Table continues  ) 4212 BRIEF REVIEWS: IMMUNE RESPONSES AGAINST CHIKV   b  y g u e  s  t   onD e  c  e m b  e r  6  ,2  0 1  7 h  t   t   p :  /   /   w w w . j  i  mm un ol   . or  g /  D o wnl   o a  d  e  d f  r  om 
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