MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2


Autoři: Mary K. McCarthy aff001;  Glennys V. Reynoso aff002;  Emma S. Winkler aff003;  Matthias Mack aff004;  Michael S. Diamond aff003;  Heather D. Hickman aff002;  Thomas E. Morrison aff001
Působiště autorů: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America aff001;  Viral Immunity and Pathogenesis Unit, Laboratory of Clinical Microbiology and Immunology, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, United States of America aff002;  Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America aff003;  Regensburg University Medical Center, Regensburg, Germany aff004;  Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America aff005;  Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America aff006;  The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, United States of America aff007
Vyšlo v časopise: MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008292
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008292

Souhrn

Humoral immune responses initiate in the lymph node draining the site of viral infection (dLN). Some viruses subvert LN B cell activation; however, our knowledge of viral hindrance of B cell responses of important human pathogens is lacking. Here, we define mechanisms whereby chikungunya virus (CHIKV), a mosquito-transmitted RNA virus that causes outbreaks of acute and chronic arthritis in humans, hinders dLN antiviral B cell responses. Infection of WT mice with pathogenic, but not acutely cleared CHIKV, induced MyD88-dependent recruitment of monocytes and neutrophils to the dLN. Blocking this influx improved lymphocyte accumulation, dLN organization, and CHIKV-specific B cell responses. Both inducible nitric oxide synthase (iNOS) and the phagocyte NADPH oxidase (Nox2) contributed to impaired dLN organization and function. Infiltrating monocytes expressed iNOS through a local IRF5- and IFNAR1-dependent pathway that was partially TLR7-dependent. Together, our data suggest that pathogenic CHIKV triggers the influx and activation of monocytes and neutrophils in the dLN that impairs virus-specific B cell responses.

Klíčová slova:

B cells – Flow cytometry – Chikungunya infection – Chikungunya virus – Lymphocytes – Monocytes – Neutrophils – Pathogens


Zdroje

1. von Andrian UH, Mempel TR. Homing and cellular traffic in lymph nodes. Nat Rev Immunol. 2003;3(11):867–78. Epub 2003/12/12. doi: 10.1038/nri1222 14668803.

2. Kuka M, Iannacone M. The role of lymph node sinus macrophages in host defense. Ann N Y Acad Sci. 2014;1319:38–46. Epub 2014/03/07. doi: 10.1111/nyas.12387 24592818.

3. Kerfoot SM, Yaari G, Patel JR, Johnson KL, Gonzalez DG, Kleinstein SH, et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity. 2011;34(6):947–60. Epub 2011/06/04. doi: 10.1016/j.immuni.2011.03.024 21636295; PubMed Central PMCID: PMC3280079.

4. Batista FD, Harwood NE. The who, how and where of antigen presentation to B cells. Nat Rev Immunol. 2009;9(1):15–27. Epub 2008/12/17. doi: 10.1038/nri2454 19079135.

5. Sammicheli S, Kuka M, Di Lucia P, de Oya NJ, De Giovanni M, Fioravanti J, et al. Inflammatory monocytes hinder antiviral B cell responses. Sci Immunol. 2016;1(4). Epub 2016/11/22. doi: 10.1126/sciimmunol.aah6789 27868108; PubMed Central PMCID: PMC5111729.

6. Gaya M, Castello A, Montaner B, Rogers N, Reis e Sousa C, Bruckbauer A, et al. Inflammation-induced disruption of SCS macrophages impairs B cell responses to secondary infection. Science. 2015;347(6222):667–72. doi: 10.1126/science.aaa1300 25657250

7. Zeng M, Haase AT, Schacker TW. Lymphoid tissue structure and HIV-1 infection: life or death for T cells. Trends Immunol. 2012;33(6):306–14. Epub 2012/05/23. doi: 10.1016/j.it.2012.04.002 22613276.

8. Morrison TE. Reemergence of chikungunya virus. J Virol. 2014;88(20):11644–7. Epub 2014/08/01. doi: 10.1128/JVI.01432-14 25078691; PubMed Central PMCID: PMC4178719.

9. McCarthy MK, Davenport BJJ, Morrison TE. Chronic Chikungunya Virus Disease. Curr Top Microbiol Immunol. 2019. Epub 2019/01/19. doi: 10.1007/82_2018_147 30656438.

10. Lum FM, Teo TH, Lee WWL, Kam YW, Renia L, Ng LFP. An Essential Role of Antibodies in the Control of Chikungunya Virus Infection. The Journal of Immunology. 2013;190(12):6295–302. doi: 10.4049/jimmunol.1300304 23670192

11. Smith SA, Silva LA, Fox JM, Flyak AI, Kose N, Sapparapu G, et al. Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe. 2015;18(1):86–95. Epub 2015/07/15. doi: 10.1016/j.chom.2015.06.009 26159721; PubMed Central PMCID: PMC4501771.

12. Pal P, Dowd KA, Brien JD, Edeling MA, Gorlatov S, Johnson S, et al. Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus. PLoS Pathog. 2013;9(4):e1003312. Epub 2013/05/03. doi: 10.1371/journal.ppat.1003312 23637602; PubMed Central PMCID: PMC3630103.

13. Couderc T, Khandoudi N, Grandadam M, Visse C, Gangneux N, Bagot S, et al. Prophylaxis and therapy for Chikungunya virus infection. J Infect Dis. 2009;200(4):516–23. Epub 2009/07/04. doi: 10.1086/600381 19572805.

14. Hawman DW, Fox JM, Ashbrook AW, May NA, Schroeder KMS, Torres RM, et al. Pathogenic Chikungunya Virus Evades B Cell Responses to Establish Persistence. Cell Rep. 2016;16(5):1326–38. Epub 2016/07/28. doi: 10.1016/j.celrep.2016.06.076 27452455; PubMed Central PMCID: PMC5003573.

15. Hawman DW, Stoermer KA, Montgomery SA, Pal P, Oko L, Diamond MS, et al. Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response. J Virol. 2013;87(24):13878–88. Epub 2013/10/18. doi: 10.1128/JVI.02666-13 24131709; PubMed Central PMCID: PMC3838294.

16. Labadie K, Larcher T, Joubert C, Mannioui A, Delache B, Brochard P, et al. Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages. J Clin Invest. 2010;120(3):894–906. Epub 2010/02/25. doi: 10.1172/JCI40104 20179353; PubMed Central PMCID: PMC2827953.

17. Messaoudi I, Vomaske J, Totonchy T, Kreklywich CN, Haberthur K, Springgay L, et al. Chikungunya virus infection results in higher and persistent viral replication in aged rhesus macaques due to defects in anti-viral immunity. PLoS Negl Trop Dis. 2013;7(7):e2343. Epub 2013/08/13. doi: 10.1371/journal.pntd.0002343 23936572; PubMed Central PMCID: PMC3723534.

18. Poo YS, Rudd PA, Gardner J, Wilson JA, Larcher T, Colle MA, et al. Multiple immune factors are involved in controlling acute and chronic chikungunya virus infection. PLoS Negl Trop Dis. 2014;8(12):e3354. Epub 2014/12/05. doi: 10.1371/journal.pntd.0003354 25474568; PubMed Central PMCID: PMC4256279.

19. Teo TH, Lum FM, Claser C, Lulla V, Lulla A, Merits A, et al. A pathogenic role for CD4+ T cells during Chikungunya virus infection in mice. J Immunol. 2013;190(1):259–69. Epub 2012/12/05. doi: 10.4049/jimmunol.1202177 23209328.

20. Uhrlaub JL, Pulko V, DeFilippis VR, Broeckel R, Streblow DN, Coleman GD, et al. Dysregulated TGF-beta Production Underlies the Age-Related Vulnerability to Chikungunya Virus. PLoS Pathog. 2016;12(10):e1005891. Epub 2016/10/14. doi: 10.1371/journal.ppat.1005891 27736984.

21. Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, Das T, Li-Pat-Yuen G, Dassa B, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol. 2010;184(10):5914–27. Epub 2010/04/21. doi: 10.4049/jimmunol.0900255 20404278.

22. Ozden S, Huerre M, Riviere JP, Coffey LL, Afonso PV, Mouly V, et al. Human muscle satellite cells as targets of Chikungunya virus infection. PLoS One. 2007;2(6):e527. Epub 2007/06/15. doi: 10.1371/journal.pone.0000527 17565380; PubMed Central PMCID: PMC1885285.

23. McCarthy MK, Davenport BJ, Reynoso GV, Lucas ED, May NA, Elmore SA, et al. Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment. JCI Insight. 2018;3(13). doi: 10.1172/jci.insight.121100DS1

24. Partidos CD, Weger J, Brewoo J, Seymour R, Borland EM, Ledermann JP, et al. Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling. Vaccine. 2011;29(16):3067–73. Epub 2011/02/09. doi: 10.1016/j.vaccine.2011.01.076 21300099; PubMed Central PMCID: PMC3081687.

25. Gorchakov R, Wang E, Leal G, Forrester NL, Plante K, Rossi SL, et al. Attenuation of Chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the E2 envelope glycoprotein. J Virol. 2012;86(11):6084–96. Epub 2012/03/30. doi: 10.1128/JVI.06449-11 22457519; PubMed Central PMCID: PMC3372191.

26. Morrison TE, Oko L, Montgomery SA, Whitmore AC, Lotstein AR, Gunn BM, et al. A Mouse Model of Chikungunya Virus-Induced Musculoskeletal Inflammatory Disease. AJPA. 2011;178(1):32–40. doi: 10.1016/j.ajpath.2010.11.018 21224040

27. Matsuzaki J, Tsuji T, Chamoto K, Takeshima T, Sendo F, Nishimura T. Successful elimination of memory-type CD8+ T cell subsets by the administration of anti-Gr-1 monoclonal antibody in vivo. Cellular Immunology. 2003;224(2):98–105. doi: 10.1016/j.cellimm.2003.08.009 14609575

28. Mack M, Cihak J, Simonis C, Luckow B, Proudfoot AEI, Plachy J, et al. Expression and Characterization of the Chemokine Receptors CCR2 and CCR5 in Mice. The Journal of Immunology. 2001;166(7):4697–704. doi: 10.4049/jimmunol.166.7.4697 11254730

29. Iijima N, Mattei LM, Iwasaki A. Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proceedings of the National Academy of Sciences. 2010;108(1):284–9. doi: 10.1073/pnas.1005201108/-/DCSupplemental 21173243; PubMed Central PMCID: PMC3017177.

30. Gresser I, Guy-Grand D, Maury C, Maunoury M. Interferon induces peripheral lymphadenopathy in mice. J Immunol. 1981;127:1569–75. 7276571

31. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. 2011;11(11):762–74. Epub 2011/10/11. doi: 10.1038/nri3070 21984070; PubMed Central PMCID: PMC3947780.

32. Deguine J, Barton GM. MyD88: a central player in innate immune signaling. F1000Prime Rep. 2014;6:97. Epub 2015/01/13. doi: 10.12703/P6-97 25580251; PubMed Central PMCID: PMC4229726.

33. Nathan C, Xie QW. Regulation of biosynthesis of nitric oxide. The Journal of biological chemistry. 1994;269(19):13725–8. 7514592.

34. Squadrito GL, Pryor WA. The formation of peroxynitrite in vivo from nitric oxide and superoxide. Chemico-biological interactions. 1995;96(2):203–6. doi: 10.1016/0009-2797(94)03591-u 7728908.

35. Lu T, Gabrilovich DI. Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res. 2012;18(18):4877–82. Epub 2012/06/22. doi: 10.1158/1078-0432.CCR-11-2939 22718858; PubMed Central PMCID: PMC3445728.

36. Majer O, Bourgeois C, Zwolanek F, Lassnig C, Kerjaschki D, Mack M, et al. Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections. PLoS Pathog. 2012;8(7):e1002811. Epub 2012/08/23. doi: 10.1371/journal.ppat.1002811 22911155; PubMed Central PMCID: PMC3406095.

37. Rudd PA, Wilson J, Gardner J, Larcher T, Babarit C, Le TT, et al. Interferon Response Factors 3 and 7 Protect against Chikungunya Virus Hemorrhagic Fever and Shock. Journal of Virology. 2012;86(18):9888–98. doi: 10.1128/JVI.00956-12 22761364

38. Schilte C, Buckwalter MR, Laird ME, Diamond MS, Schwartz O, Albert ML. Cutting Edge: Independent Roles for IRF-3 and IRF-7 in Hematopoietic and Nonhematopoietic Cells during Host Response to Chikungunya Infection. The Journal of Immunology. 2012;188(7):2967–71. doi: 10.4049/jimmunol.1103185 22371392

39. Schoenemeyer A, Barnes BJ, Mancl ME, Latz E, Goutagny N, Pitha PM, et al. The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling. J Biol Chem. 2005;280(17):17005–12. Epub 2005/02/08. doi: 10.1074/jbc.M412584200 15695821.

40. Dai P, Cao H, Merghoub T, Avogadri F, Wang W, Parikh T, et al. Myxoma virus induces type I interferon production in murine plasmacytoid dendritic cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-dependent pathway. J Virol. 2011;85(20):10814–25. Epub 2011/08/13. doi: 10.1128/JVI.00104-11 21835795; PubMed Central PMCID: PMC3187486.

41. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434(7030):243–9. Epub 2005/02/23. doi: 10.1038/nature03308 15665823

42. Duffau P, Menn-Josephy H, Cuda CM, Dominguez S, Aprahamian TR, Watkins AA, et al. Promotion of Inflammatory Arthritis by Interferon Regulatory Factor 5 in a Mouse Model. Arthritis Rheumatol. 2015;67(12):3146–57. Epub 2015/09/01. doi: 10.1002/art.39321 26315890; PubMed Central PMCID: PMC4661118.

43. Ouyang X, Negishi H, Takeda R, Fujita Y, Taniguchi T, Honda K. Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation. Biochem Biophys Res Commun. 2007;354(4):1045–51. Epub 2007/02/06. doi: 10.1016/j.bbrc.2007.01.090 17275788.

44. Mack EA, Kallal LE, Demers DA, Biron CA. Type 1 interferon induction of natural killer cell gamma interferon production for defense during lymphocytic choriomeningitis virus infection. MBio. 2011;2(4). Epub 2011/08/11. doi: 10.1128/mBio.00169-11 21828218; PubMed Central PMCID: PMC3150756.

45. Lazear HM, Lancaster A, Wilkins C, Suthar MS, Huang A, Vick SC, et al. IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling. PLoS Pathog. 2013;9(1):e1003118. Epub 2013/01/10. doi: 10.1371/journal.ppat.1003118 23300459; PubMed Central PMCID: PMC3536698.

46. Schilte C, Couderc T, Chrétien F, Sourisseau M, Gangneux N, Guivel-Benhassine F, et al. Type I IFN controls chikungunya virus via its action on nonhematopoietic cells. Journal of Experimental Medicine. 2010;207(2):429–42. doi: 10.1084/jem.20090851 20123960

47. Detienne S, Welsby I, Collignon C, Wouters S, Coccia M, Delhaye S, et al. Central Role of CD169+ Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01. Scientific Reports. 2016;6:39475. doi: 10.1038/srep39475 27996000; PubMed Central PMCID: PMC5172233.

48. Sagoo P, Garcia Z, Breart B, Lemaître F, Michonneau D, Albert ML, et al. In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity. Nature Medicine. 2015;22(1):64–71. doi: 10.1038/nm.4016 26692332

49. Van Winkle JA, Robinson BA, Peters AM, Li L, Nouboussi RV, Mack M, et al. Persistence of Systemic Murine Norovirus Is Maintained by Inflammatory Recruitment of Susceptible Myeloid Cells. Cell Host & Microbe. 2018;24(5):665–76.e4. doi: 10.1016/j.chom.2018.10.003 30392829

50. Lee PY, Li Y, Kumagai Y, Xu Y, Weinstein JS, Kellner ES, et al. Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation. AJPA. 2010;175(5):2023–33. doi: 10.2353/ajpath.2009.090328 19808647

51. Miller LS, O'Connell RM, Gutierrez MA, Pietras EM, Shahangian A, Gross CE, et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity. 2006;24(1):79–91. Epub 2006/01/18. doi: 10.1016/j.immuni.2005.11.011 16413925.

52. Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E, et al. IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol. 2011;187(9):4835–43. Epub 2011/09/21. doi: 10.4049/jimmunol.1102048 21930960.

53. Schmitz N, Kurrer M, Bachmann MF, Kopf M. Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol. 2005;79(10):6441–8. Epub 2005/04/29. doi: 10.1128/JVI.79.10.6441-6448.2005 15858027; PubMed Central PMCID: PMC1091664.

54. Stifter SA, Bhattacharyya N, Pillay R, Florido M, Triccas JA, Britton WJ, et al. Functional Interplay between Type I and II Interferons Is Essential to Limit Influenza A Virus-Induced Tissue Inflammation. PLoS Pathog. 2016;12(1):e1005378. Epub 2016/01/06. doi: 10.1371/journal.ppat.1005378 26731100; PubMed Central PMCID: PMC4701664.

55. Fallet B, Narr K, Ertuna YI, Remy M, Sommerstein R, Cornille K, et al. Interferon-driven deletion of antiviral B cells at the onset of chronic infection. Science immunology. 2016;1(4). doi: 10.1126/sciimmunol.aah6817 PubMed Central PMCID: PMC5115616. 27872905

56. Moseman EA, Wu T, de la Torre JC, Schwartzberg PL, McGavern DB. Type I interferon suppresses virus-specific B cell responses by modulating CD8+ T cell differentiation. Science immunology. 2016;1(4):eaah3565. PubMed Central PMCID: PMC5089817. 27812556

57. Seo S-U, Kwon H-J, Ko H-J, Byun Y-H, Seong BL, Uematsu S, et al. Type I Interferon Signaling Regulates Ly6Chi Monocytes and Neutrophils during Acute Viral Pneumonia in Mice. PLoS Pathogens. 2011;7(2):e1001304. doi: 10.1371/journal.ppat.1001304 21383977

58. Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host & Microbe. 2016;19(2):181–93. doi: 10.1016/j.chom.2016.01.007 26867177

59. Barnes BJ, Moore PA, Pitha PM. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem. 2001;276(26):23382–90. Epub 2001/04/17. doi: 10.1074/jbc.M101216200 11303025.

60. Barnes BJ, Kellum MJ, Field AE, Pitha PM. Multiple Regulatory Domains of IRF-5 Control Activation, Cellular Localization, and Induction of Chemokines That Mediate Recruitment of T Lymphocytes. Molecular and Cellular Biology. 2002;22(16):5721–40. doi: 10.1128/MCB.22.16.5721-5740.2002 12138184

61. Thackray LB, Shrestha B, Richner JM, Miner JJ, Pinto AK, Lazear HM, et al. Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile virus infection. J Virol. 2014;88(19):11007–21. Epub 2014/07/18. doi: 10.1128/JVI.01545-14 25031348; PubMed Central PMCID: PMC4178807.

62. Chow KT, Wilkins C, Narita M, Green R, Knoll M, Loo YM, et al. Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells. J Immunol. 2018;201(10):3036–50. Epub 2018/10/10. doi: 10.4049/jimmunol.1800221 30297339; PubMed Central PMCID: PMC6219909.

63. Coccia EM, Severa M, Giacomini E, Monneron D, Remoli ME, Julkunen I, et al. Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur J Immunol. 2004;34(3):796–805. Epub 2004/03/03. doi: 10.1002/eji.200324610 14991609.

64. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011;12(3):231–8. Epub 2011/01/18. doi: 10.1038/ni.1990 21240265.

65. Weiss M, Blazek K, Byrne AJ, Perocheau DP, Udalova IA. IRF5 is a specific marker of inflammatory macrophages in vivo. Mediators Inflamm. 2013;2013:245804. Epub 2014/01/24. doi: 10.1155/2013/245804 24453413; PubMed Central PMCID: PMC3885211.

66. Ericson JA, Duffau P, Yasuda K, Ortiz-Lopez A, Rothamel K, Rifkin IR, et al. Gene expression during the generation and activation of mouse neutrophils: implication of novel functional and regulatory pathways. PLoS One. 2014;9(10):e108553. Epub 2014/10/04. doi: 10.1371/journal.pone.0108553 25279834; PubMed Central PMCID: PMC4184787.

67. Ashbrook AW, Burrack KS, Silva LA, Montgomery SA, Heise MT, Morrison TE, et al. Residue 82 of the Chikungunya Virus E2 Attachment Protein Modulates Viral Dissemination and Arthritis in Mice. Journal of Virology. 2014;88(21):12180–92. doi: 10.1128/JVI.01672-14 25142598

68. Morrison TE, Oko L, Montgomery SA, Whitmore AC, Lotstein AR, Gunn BM, et al. A Mouse Model of Chikungunya Virus–Induced Musculoskeletal Inflammatory Disease. AJPA. 2011;178(1):32–40. doi: 10.1016/j.ajpath.2010.11.018 21224040

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