Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells


Mosquito-transmitted chikungunya virus (CHIKV), Ross River virus (RRV), and related alphaviruses cause epidemics involving millions of persons, such as on-going CHIKV outbreaks in the Caribbean and Central and South America. Infection with these viruses results in severe pain due to inflammation of musculoskeletal tissues that can persist for months and even years. There are no specific therapeutics or licensed vaccines for these viruses. Suppressive myeloid cells have been shown to inhibit anti-pathogen immune responses, including T cell responses, which can promote chronic disease. We showed previously that a gene associated with suppressive myeloid cells, arginase 1 (Arg1), was induced in musculoskeletal tissues and macrophages of mice infected with RRV or CHIKV, and mice that lacked Arg1 expression in myeloid cells had reduced viral loads at late times post-infection. Here, we demonstrate that Arg1 is induced in PBMCs isolated from CHIKV-infected patients, and Arg1 expression is associated with viral loads. Moreover, we found that Arg1-expressing myeloid cells inhibit the activation and function of antiviral T cells in RRV-infected mice. These studies underscore the role of suppressive myeloid cells in modulating the T cell response to arthritogenic alphaviruses and provide a therapeutic target to enhance viral clearance and potentially limit chronic disease.


Vyšlo v časopise: Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005191
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1005191

Souhrn

Mosquito-transmitted chikungunya virus (CHIKV), Ross River virus (RRV), and related alphaviruses cause epidemics involving millions of persons, such as on-going CHIKV outbreaks in the Caribbean and Central and South America. Infection with these viruses results in severe pain due to inflammation of musculoskeletal tissues that can persist for months and even years. There are no specific therapeutics or licensed vaccines for these viruses. Suppressive myeloid cells have been shown to inhibit anti-pathogen immune responses, including T cell responses, which can promote chronic disease. We showed previously that a gene associated with suppressive myeloid cells, arginase 1 (Arg1), was induced in musculoskeletal tissues and macrophages of mice infected with RRV or CHIKV, and mice that lacked Arg1 expression in myeloid cells had reduced viral loads at late times post-infection. Here, we demonstrate that Arg1 is induced in PBMCs isolated from CHIKV-infected patients, and Arg1 expression is associated with viral loads. Moreover, we found that Arg1-expressing myeloid cells inhibit the activation and function of antiviral T cells in RRV-infected mice. These studies underscore the role of suppressive myeloid cells in modulating the T cell response to arthritogenic alphaviruses and provide a therapeutic target to enhance viral clearance and potentially limit chronic disease.


Zdroje

1. Suhrbier A, Jaffar-Bandjee MC, Gasque P (2012) Arthritogenic alphaviruses—an overview. Nat Rev Rheumatol 8: 420–429. doi: 10.1038/nrrheum.2012.64 22565316

2. Josseran L, Paquet C, Zehgnoun A, Caillere N, Le Tertre A, et al. (2006) Chikungunya disease outbreak, Reunion Island. Emerg Infect Dis 12: 1994–1995. 17354339

3. Kaur P, Ponniah M, Murhekar MV, Ramachandran V, Ramachandran R, et al. (2008) Chikungunya outbreak, South India, 2006. Emerg Infect Dis 14: 1623–1625. doi: 10.3201/eid1410.070569 18826830

4. Laras K, Sukri NC, Larasati RP, Bangs MJ, Kosim R, et al. (2005) Tracking the re-emergence of epidemic chikungunya virus in Indonesia. Trans R Soc Trop Med Hyg 99: 128–141. 15693148

5. AbuBakar S, Sam IC, Wong PF, MatRahim N, Hooi PS, et al. (2007) Reemergence of endemic Chikungunya, Malaysia. Emerg Infect Dis 13: 147–149. 17370532

6. Leo YS, Chow AL, Tan LK, Lye DC, Lin L, et al. (2009) Chikungunya outbreak, Singapore, 2008. Emerg Infect Dis 15: 836–837. doi: 10.3201/eid1505.081390 19402989

7. Queyriaux B, Armengaud A, Jeannin C, Couturier E, Peloux-Petiot F (2008) Chikungunya in Europe. Lancet 371: 723–724. doi: 10.1016/S0140-6736(08)60337-2 18313498

8. Fischer M, Staples JE (2014) Notes from the field: chikungunya virus spreads in the Americas—Caribbean and South America, 2013–2014. MMWR Morb Mortal Wkly Rep 63: 500–501. 24898168

9. Leparc-Goffart I, Nougairede A, Cassadou S, Prat C, de Lamballerie X (2014) Chikungunya in the Americas. Lancet 383: 514. doi: 10.1016/S0140-6736(14)60185-9 24506907

10. Morrison TE (2014) Reemergence of chikungunya virus. J Virol 88: 11644–11647. doi: 10.1128/JVI.01432-14 25078691

11. Suhrbier A, Jaffar-Bandjee MC, Gasque P Arthritogenic alphaviruses—an overview. Nat Rev Rheumatol 8: 420–429. doi: 10.1038/nrrheum.2012.64 22565316

12. Aaskov JG, Mataika JU, Lawrence GW, Rabukawaqa V, Tucker MM, et al. (1981) An epidemic of Ross River virus infection in Fiji, 1979. Am J Trop Med Hyg 30: 1053–1059. 7283004

13. Rosen L, Gubler DJ, Bennett PH (1981) Epidemic polyarthritis (Ross River) virus infection in the Cook Islands. Am J Trop Med Hyg 30: 1294–1302. 7325286

14. Tesh RB, McLean RG, Shroyer DA, Calisher CH, Rosen L (1981) Ross River virus (Togaviridae: Alphavirus) infection (epidemic polyarthritis) in American Samoa. Trans R Soc Trop Med Hyg 75: 426–431. 7324110

15. Suhrbier A, La Linn M (2004) Clinical and pathologic aspects of arthritis due to Ross River virus and other alphaviruses. Curr Opin Rheumatol 16: 374–379. 15201600

16. Simon F, Parola P, Grandadam M, Fourcade S, Oliver M, et al. (2007) Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore) 86: 123–137.

17. Borgherini G, Poubeau P, Jossaume A, Gouix A, Cotte L, et al. (2008) Persistent arthralgia associated with chikungunya virus: a study of 88 adult patients on reunion island. Clin Infect Dis 47: 469–475. doi: 10.1086/590003 18611153

18. Lakshmi V, Neeraja M, Subbalaxmi MV, Parida MM, Dash PK, et al. (2008) Clinical features and molecular diagnosis of Chikungunya fever from South India. Clin Infect Dis 46: 1436–1442. doi: 10.1086/529444 18419449

19. Sissoko D, Malvy D, Ezzedine K, Renault P, Moscetti F, et al. (2009) Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl Trop Dis 3: e389. doi: 10.1371/journal.pntd.0000389 19274071

20. Larrieu S, Pouderoux N, Pistone T, Filleul L, Receveur MC, et al. (2010) Factors associated with persistence of arthralgia among Chikungunya virus-infected travellers: report of 42 French cases. J Clin Virol 47: 85–88. doi: 10.1016/j.jcv.2009.11.014 20004145

21. Schilte C, Staikowsky F, Couderc T, Madec Y, Carpentier F, et al. (2013) Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLoS Negl Trop Dis 7: e2137. doi: 10.1371/journal.pntd.0002137 23556021

22. Ozden S, Huerre M, Riviere JP, Coffey LL, Afonso PV, et al. (2007) Human muscle satellite cells as targets of Chikungunya virus infection. PLoS One 2: e527. 17565380

23. Morrison TE, Oko L, Montgomery SA, Whitmore AC, Lotstein AR, et al. (2011) A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence. Am J Pathol 178: 32–40. doi: 10.1016/j.ajpath.2010.11.018 21224040

24. Hawman DW, Stoermer KA, Montgomery SA, Pal P, Oko L, et al. (2013) Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response. J Virol 87: 13878–13888. doi: 10.1128/JVI.02666-13 24131709

25. Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, Das T, Li-Pat-Yuen G, et al. (2010) Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol 184: 5914–5927. doi: 10.4049/jimmunol.0900255 20404278

26. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5: 953–964. 16322748

27. Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27: 451–483. doi: 10.1146/annurev.immunol.021908.132532 19105661

28. Munder M, Schneider H, Luckner C, Giese T, Langhans CD, et al. (2006) Suppression of T-cell functions by human granulocyte arginase. Blood 108: 1627–1634. 16709924

29. Vercelli D (2003) Arginase: marker, effector, or candidate gene for asthma? J Clin Invest 111: 1815–1817. 12813015

30. Kropf P, Fuentes JM, Fahnrich E, Arpa L, Herath S, et al. (2005) Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo. FASEB J 19: 1000–1002. 15811879

31. Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, et al. (2001) Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol 167: 6533–6544. 11714822

32. Zea AH, Culotta KS, Ali J, Mason C, Park HJ, et al. (2006) Decreased expression of CD3zeta and nuclear transcription factor kappa B in patients with pulmonary tuberculosis: potential mechanisms and reversibility with treatment. J Infect Dis 194: 1385–1393. 17054067

33. Cloke TE, Garvey L, Choi BS, Abebe T, Hailu A, et al. (2010) Increased level of arginase activity correlates with disease severity in HIV-seropositive patients. J Infect Dis 202: 374–385. doi: 10.1086/653736 20575659

34. Sandalova E, Laccabue D, Boni C, Watanabe T, Tan A, et al. (2012) Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. Gastroenterology 143: 78–87 e73. doi: 10.1053/j.gastro.2012.03.041 22475535

35. Munder M (2009) Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 158: 638–651. doi: 10.1111/j.1476-5381.2009.00291.x 19764983

36. Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5: 641–654. 16056256

37. Rodriguez PC, Ochoa AC (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222: 180–191. doi: 10.1111/j.1600-065X.2008.00608.x 18364002

38. El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, et al. (2008) Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9: 1399–1406. doi: 10.1038/ni.1671 18978793

39. Bronte V, Serafini P, De Santo C, Marigo I, Tosello V, et al. (2003) IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 170: 270–278. 12496409

40. Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, et al. (2005) Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res 65: 3044–3048. 15833831

41. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, et al. (2009) Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 5: e1000371. doi: 10.1371/journal.ppat.1000371 19360123

42. Qin A, Cai W, Pan T, Wu K, Yang Q, et al. (2013) Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J Virol 87: 1477–1490. doi: 10.1128/JVI.01759-12 23152536

43. Zeng QL, Yang B, Sun HQ, Feng GH, Jin L, et al. (2014) Myeloid-derived suppressor cells are associated with viral persistence and downregulation of TCR zeta chain expression on CD8(+) T cells in chronic hepatitis C patients. Mol Cells 37: 66–73. doi: 10.14348/molcells.2014.2282 24552712

44. Stoermer KA, Burrack A, Oko L, Montgomery SA, Borst LB, et al. (2012) Genetic ablation of arginase 1 in macrophages and neutrophils enhances clearance of an arthritogenic alphavirus. J Immunol 189: 4047–4059. doi: 10.4049/jimmunol.1201240 22972923

45. Chow A, Her Z, Ong EK, Chen JM, Dimatatac F, et al. (2011) Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J Infect Dis 203: 149–157. doi: 10.1093/infdis/jiq042 21288813

46. Thon-Hon VG, Denizot M, Li-Pat-Yuen G, Giry C, Jaffar-Bandjee MC, et al. (2012) Deciphering the differential response of two human fibroblast cell lines following Chikungunya virus infection. Virol J 9: 213. doi: 10.1186/1743-422X-9-213 22992396

47. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, et al. (2004) Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 64: 5839–5849. 15313928

48. Modolell M, Choi BS, Ryan RO, Hancock M, Titus RG, et al. (2009) Local suppression of T cell responses by arginase-induced L-arginine depletion in nonhealing leishmaniasis. PLoS Negl Trop Dis 3: e480. doi: 10.1371/journal.pntd.0000480 19597544

49. Rodriguez PC, Quiceno DG, Ochoa AC (2007) L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109: 1568–1573. 17023580

50. Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, et al. (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13: 828–835. 17603493

51. Burrack KS, Montgomery SA, Homann D, Morrison TE (2015) CD8+ T cells control Ross River virus infection in musculoskeletal tissues of infected mice. J Immunol 194: 678–689. doi: 10.4049/jimmunol.1401833 25488988

52. Wherry EJ, Ahmed R (2004) Memory CD8 T-cell differentiation during viral infection. J Virol 78: 5535–5545. 15140950

53. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12: 253–268. doi: 10.1038/nri3175 22437938

54. Binder GK, Griffin DE (2001) Interferon-gamma-mediated site-specific clearance of alphavirus from CNS neurons. Science 293: 303–306. 11452126

55. Teo TH, Lum FM, Claser C, Lulla V, Lulla A, et al. (2013) A pathogenic role for CD4+ T cells during Chikungunya virus infection in mice. J Immunol 190: 259–269. doi: 10.4049/jimmunol.1202177 23209328

56. Tough DF, Borrow P, Sprent J (1996) Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272: 1947–1950. 8658169

57. Skon CN, Lee JY, Anderson KG, Masopust D, Hogquist KA, et al. (2013) Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8(+) T cells. Nature Immunology 14: 1285-+. doi: 10.1038/ni.2745 24162775

58. Zajac AJ, Harrington LE (2014) Tissue-resident T cells lose their S1P1 exit visas. Cell Mol Immunol 11: 221–223. doi: 10.1038/cmi.2014.7 24561454

59. Slifka MK, Whitton JL (2000) Antigen-specific regulation of T cell-mediated cytokine production. Immunity 12: 451–457. 10843378

60. Teng TS, Foo SS, Simamarta D, Lum FM, Teo TH, et al. (2012) Viperin restricts chikungunya virus replication and pathology. J Clin Invest 122: 4447–4460. doi: 10.1172/JCI63120 23160199

61. Ng LF, Chow A, Sun YJ, Kwek DJ, Lim PL, et al. (2009) IL-1beta, IL-6, and RANTES as biomarkers of Chikungunya severity. PLoS One 4: e4261. doi: 10.1371/journal.pone.0004261 19156204

62. Doherty RI, Whitehead RH, Gorman BM, O'Gower AK (1963) The isolation of a third group A arbovirus in Australia, with preliminary observations on its relationships to epidemic polyarthritis. Aust J Sci 26: 183–184.

63. Kuhn RJ, Niesters HG, Hong Z, Strauss JH (1991) Infectious RNA transcripts from Ross River virus cDNA clones and the construction and characterization of defined chimeras with Sindbis virus. Virology 182: 430–441. 1673812

64. Dalgarno L, Rice CM, Strauss JH (1983) Ross River virus 26 s RNA: complete nucleotide sequence and deduced sequence of the encoded structural proteins. Virology 129: 170–187. 6310876

65. Jupille HJ, Medina-Rivera M, Hawman DW, Oko L, Morrison TE A tyrosine-to-histidine switch at position 18 of the Ross River virus E2 glycoprotein is a determinant of virus fitness in disparate hosts. J Virol 87: 5970–5984. doi: 10.1128/JVI.03326-12 23514884

66. Marsolais D, Hahm B, Walsh KB, Edelmann KH, McGavern D, et al. (2009) A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection. Proc Natl Acad Sci U S A 106: 1560–1565. doi: 10.1073/pnas.0812689106 19164548

67. Bessaud M, Peyrefitte CN, Pastorino BA, Tock F, Merle O, et al. (2006) Chikungunya virus strains, Reunion Island outbreak. Emerg Infect Dis 12: 1604–1606. 17176585

68. Morrison TE, Whitmore AC, Shabman RS, Lidbury BA, Mahalingam S, et al. (2006) Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis. J Virol 80: 737–749. 16378976

69. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408. 11846609

70. Teng TS, Foo SS, Simamarta D, Lum FM, Teo TH, et al. Viperin restricts chikungunya virus replication and pathology. J Clin Invest 122: 4447–4460. doi: 10.1172/JCI63120 23160199

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa