CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection
Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.
Vyšlo v časopise:
CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection. PLoS Pathog 8(5): e32767. doi:10.1371/journal.ppat.1002710
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002710
Souhrn
Immunological checkpoints, such as the inhibitory CD200 receptor (CD200R), play a dual role in balancing the immune system during microbial infection. On the one hand these inhibitory signals prevent excessive immune mediated pathology but on the other hand they may impair clearance of the pathogen. We studied the influence of the inhibitory CD200-CD200R axis on clearance and pathology in two different virus infection models. We find that lack of CD200R signaling strongly enhances type I interferon (IFN) production and viral clearance and improves the outcome of mouse hepatitis corona virus (MHV) infection, particularly in female mice. MHV clearance is known to be dependent on Toll like receptor 7 (TLR7)-mediated type I IFN production and sex differences in TLR7 responses previously have been reported for humans. We therefore hypothesize that CD200R ligation suppresses TLR7 responses and that release of this inhibition enlarges sex differences in TLR7 signaling. This hypothesis is supported by our findings that in vivo administration of synthetic TLR7 ligand leads to enhanced type I IFN production, particularly in female Cd200−/− mice and that CD200R ligation inhibits TLR7 signaling in vitro. In influenza A virus infection we show that viral clearance is determined by sex but not by CD200R signaling. However, absence of CD200R in influenza A virus infection results in enhanced lung neutrophil influx and pathology in females. Thus, CD200-CD200R and sex are host factors that together determine the outcome of viral infection. Our data predict a sex bias in both beneficial and pathological immune responses to virus infection upon therapeutic targeting of CD200-CD200R.
Zdroje
1. GorczynskiRM 2005 CD200 and its receptors as targets for immunoregulation. Curr Opin Investig Drugs 6 483 488
2. PrestonSWrightGJStarrKBarclayANBrownMH 1997 The leukocyte/neuron cell surface antigen OX2 binds to a ligand on macrophages. Eur J Immmunol 27 1911 1918
3. WrightGJCherwinskiHFoster-CuevasMBrookeGPuklavecMJ 2003 Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J Immunol 171 3034 3046
4. RijkersESKDe RuiterTBaridiAVeningaHHoekRM 2008 The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes. Mol Immunol 45 1126 1135
5. MihrshahiRBarclayANBrownMH 2009 Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J Immunol 183 4879 4886
6. BarclayANWrightGJBrookeGBrownMH 2002 CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23 285 290
7. HatherleyDCherwinskiHMoshrefMBarclayAN 2005 Recombinant CD200 protein does not bind activating proteins closely related to CD200 receptor. J Immunol 175 2469 2474
8. HoekRMRuulsSRMurphyCAWrightGJGoddardR 2000 Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290 1768 1771
9. MukhopadhyaySPluddemannAHoeJCWilliamsKJVarinA 2010 Immune inhibitory ligand CD200 induction by TLRs and NLRs limits macrophage activation to protect the host from meningococcal septicemia. Cell Host Microbe 8 236 247
10. SnelgroveRJGouldingJDidierlaurentAMLyongaDVekariaS 2008 A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol 9 1074 1083
11. RygielTPRijkersESdeRTStolteEHvan dV 2009 Lack of CD200 enhances pathological T cell responses during influenza infection. J Immunol 183 1990 1996
12. Cervantes-BarraganLZustRWeberFSpiegelMLangKS 2007 Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon. Blood 109 1131 1137
13. LangPACervantes-BarraganLVerschoorANavariniAARecherM 2009 Hematopoietic cell-derived interferon controls viral replication and virus-induced disease. Blood 113 1045 1052
14. RaabenMPrinsHJMartensACRottierPJde HaanCA 2009 Non-invasive imaging of mouse hepatitis coronavirus infection reveals determinants of viral replication and spread in vivo. Cell Microbiol 11 825 841
15. RaabenMGrinwisGCRottierPJde HaanCA 2010 The proteasome inhibitor Velcade enhances rather than reduces disease in mouse hepatitis coronavirus-infected mice. J Virol 84 7880 7885
16. BerghoferBFrommerTHaleyGFinkLBeinG 2006 TLR7 ligands induce higher IFN-alpha production in females. J Immunol 177 2088 2096
17. MeierAChangJJChanESPollardRBSidhuHK 2009 Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 15 955 959
18. HemmiHKaishoTTakeuchiOSatoSSanjoH 2002 Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3 196 200
19. KleinSLJedlickaAPekoszA 2010 The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis 10 338 349
20. CarrelLWillardHF 2005 X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434 400 404
21. BoudakovILiuJFanNGulayPWongK 2007 Mice lacking CD200R1 show absence of suppression of lipopolysaccharide-induced tumor necrosis factor-alpha and mixed leukocyte culture responses by CD200. Transplantation 84 251 257
22. CostelloDALyonsADenieffeSBrowneTCCoxFF 2011 Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice: A role for Toll-like receptor activation. J Biol Chem 286 34722 34732
23. ZhangSPhillipsJH 2006 Identification of tyrosine residues crucial for CD200R-mediated inhibition of mast cell activation. J Leukoc Biol 79 363 368
24. ZhangSCherwinskiHSedgwickJDPhillipsJH 2004 Molecular mechanisms of CD200 inhibition of mast cell activation. J Immunol 173 6786 6793
25. WangJPBowenGNPaddenCCernyAFinbergRW 2008 Toll-like receptor-mediated activation of neutrophils by influenza A virus. Blood 112 2028 2034
26. GeurtsvanKesselCHWillartMAvan RijtLSMuskensFKoolM 2008 Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells. J Exp Med 205 1621 1634
27. DieboldSSKaishoTHemmiHAkiraSReis e SousaC 2004 Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA. Science 303 1529 1531
28. JewellNAVaghefiNMertzSEAkterPPeeblesRSJr 2007 Differential type I interferon induction by respiratory syncytial virus and influenza a virus in vivo. J Virol 81 9790 9800
29. TonksAHillsRWhitePRosieBMillsKI 2007 CD200 as a prognostic factor in acute myeloid leukaemia. Leukemia 21 566 568
30. MoreauxJHoseDRemeTJourdanEHundemerM 2006 CD200 is a new prognostic factor in multiple myeloma. Blood 108 4194 4197
31. KleinSLPassarettiCAnkerMOlukoyaPPekoszA 2010 The impact of sex, gender and pregnancy on 2009 H1N1 disease. Biol Sex Differ 1 5
32. KayaliGWebbyRJDucatezMFEl SheshenyRAKandeilAM 2011 The epidemiological and molecular aspects of influenza H5N1 viruses at the human-animal interface in Egypt. PLoS One 6 e17730
33. LeongHNEarnestALimHHChinCFTanCS 2006 SARS in Singapore–predictors of disease severity. Ann Acad Med Singapore 35 326 331
34. KarlbergJChongDSLaiWY 2004 Do men have a higher case fatality rate of severe acute respiratory syndrome than women do? Am J Epidemiol 159 229 231
35. FishEN 2008 The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol 8 737 744
36. FarzadeganHHooverDRAstemborskiJLylesCMMargolickJB 1998 Sex differences in HIV-1 viral load and progression to AIDS. Lancet 352 1510 1514
37. KimAMTingenCMWoodruffTK 2010 Sex bias in trials and treatment must end. Nature 465 688 689
38. RaabenMEinerhandAWTaminiauLJvanHMBoumaJ 2007 Cyclooxygenase activity is important for efficient replication of mouse hepatitis virus at an early stage of infection. Virol J 4 55
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2012 Číslo 5
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- In Vitro and In Vivo Isolation and Characterization of Duvenhage Virus
- Type III Secretion in : Injectisome or Not?
- The [Het-s] Prion, an Amyloid Fold as a Cell Death Activation Trigger
- CD200 Receptor Controls Sex-Specific TLR7 Responses to Viral Infection