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Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis


Cryptococcus is an important cause of fungal meningitis with significant mortality globally. Susceptibility to the fungus in humans has been related to T-lymphocyte defects in HIV-infected individuals, but little is known about possible immune defects in non HIV-infected patients including previously healthy individuals. This latter group also has some of the worst response rates to therapy with almost a third dying in the United States, despite available therapy. Here we conducted the first detailed immunological analysis of non-HIV apparently immunocompetent individuals with active cryptococcal disease. In contrast to HIV-infected individuals, these studies identified a highly activated antigen-presenting dendritic cell population within CSF, accompanied by a highly active T-lymphocyte population with potentially damaging inflammatory cytokine responses. Furthermore, elevated levels of CSF neurofilament light chains (NFL), a marker of axonal damage in severe central nervous system infections suggest a dysfunctional role to this acute inflammatory state. Paradoxically, CSF macrophage proportions were reduced in patients with severe disease and biopsy and autopsy samples identified alternatively activated tissue macrophage populations that failed to appropriately phagocytose fungal cells. Our study thus provides new insights into the susceptibility to human cryptococcal disease and identifies a paradoxically active T-lymphocyte response that may be amenable to adjunctive immunomodulation to improve treatment outcomes in this high-mortality disease.


Vyšlo v časopise: Paradoxical Immune Responses in Non-HIV Cryptococcal Meningitis. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004884
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004884

Souhrn

Cryptococcus is an important cause of fungal meningitis with significant mortality globally. Susceptibility to the fungus in humans has been related to T-lymphocyte defects in HIV-infected individuals, but little is known about possible immune defects in non HIV-infected patients including previously healthy individuals. This latter group also has some of the worst response rates to therapy with almost a third dying in the United States, despite available therapy. Here we conducted the first detailed immunological analysis of non-HIV apparently immunocompetent individuals with active cryptococcal disease. In contrast to HIV-infected individuals, these studies identified a highly activated antigen-presenting dendritic cell population within CSF, accompanied by a highly active T-lymphocyte population with potentially damaging inflammatory cytokine responses. Furthermore, elevated levels of CSF neurofilament light chains (NFL), a marker of axonal damage in severe central nervous system infections suggest a dysfunctional role to this acute inflammatory state. Paradoxically, CSF macrophage proportions were reduced in patients with severe disease and biopsy and autopsy samples identified alternatively activated tissue macrophage populations that failed to appropriately phagocytose fungal cells. Our study thus provides new insights into the susceptibility to human cryptococcal disease and identifies a paradoxically active T-lymphocyte response that may be amenable to adjunctive immunomodulation to improve treatment outcomes in this high-mortality disease.


Zdroje

1. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, et al. (2009) Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. Aids 23: 525–530. doi: 10.1097/QAD.0b013e328322ffac 19182676

2. Kambugu A, Meya DB, Rhein J, O'Brien M, Janoff EN, et al. (2008) Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 46: 1694–1701. doi: 10.1086/587667 18433339

3. Wajanga BM, Kalluvya S, Downs JA, Johnson WD, Fitzgerald DW, et al. (2011) Universal screening of Tanzanian HIV-infected adult inpatients with the serum cryptococcal antigen to improve diagnosis and reduce mortality: an operational study. J Int AIDS Soc 14: 48. doi: 10.1186/1758-2652-14-48 21988905

4. Brizendine KD, Baddley JW, Pappas PG (2013) Predictors of mortality and differences in clinical features among patients with Cryptococcosis according to immune status. PLoS One 8: e60431. doi: 10.1371/journal.pone.0060431 23555970

5. Pyrgos V, Seitz A, Steiner C, Prevots D, Williamson PR (2013) Epidemiology of Cryptococcal meningitis in the US: 1997–2009. PloSOne 8(2): e56269. doi: 10.1371/journal.pone.0056269 23457543

6. Bratton EW, El Husseini N, Chastain CA, Lee MS, Poole C, et al. (2012) Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. PLoS One 7: e43582. doi: 10.1371/journal.pone.0043582 22937064

7. Jarvis JN, Bicanic T, Loyse A, Namarika D, Jackson A, et al. (2014) Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes. Clin Infect Dis 58: 736–745. doi: 10.1093/cid/cit794 24319084

8. Day JN, Chau TT, Lalloo DG (2013) Combination antifungal therapy for cryptococcal meningitis. N Engl J Med 368: 2522–2523. doi: 10.1056/NEJMc1305981#SA1 23802522

9. Jarvis JN, Meintjes G, Rebe K, Williams GN, Bicanic T, et al. (2012) Adjunctive interferon-gamma immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS 26: 1105–1113. doi: 10.1097/QAD.0b013e3283536a93 22421244

10. Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, et al. (2004) Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis 189: 2185–2191. 15181565

11. Jarvis JN, Casazza JP, Stone HH, Meintjes G, Lawn SD, et al. (2013) The phenotype of the Cryptococcus-specific CD4+ memory T-cell response is associated with disease severity and outcome in HIV-associated cryptococcal meningitis. J Infect Dis 207: 1817–1828. doi: 10.1093/infdis/jit099 23493728

12. Diamond RD, Bennett JE (1974) Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 80: 176–181. 4811791

13. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, et al. (2010) Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 50: 291–322. doi: 10.1086/649858 20047480

14. Chen SC, Korman TM, Slavin MA, Marriott D, Byth K, et al. (2013) Antifungal therapy and management of complications of cryptococcosis due to Cryptococcus gattii. Clin Infect Dis 57: 543–551. doi: 10.1093/cid/cit341 23697747

15. Pirofski LA, Casadevall A (2008) The damage-response framework of microbial pathogenesis and infectious diseases. Adv Exp Med Biol 635: 135–146. doi: 10.1007/978-0-387-09550-9_11 18841709

16. Casadevall A, Pirofski LA (2014) Microbiology: Ditch the term pathogen. Nature 516: 165–166. doi: 10.1038/516165a 25503219

17. Day J, Imran D, Ganiem AR, Tjahjani N, Wahyuningsih R, et al. (2014) CryptoDex: a randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial. Trials 15: 441. doi: 10.1186/1745-6215-15-441 25391338

18. Hu Z, Wei H, Meng F, Xu C, Cheng C, et al. (2013) Recurrent cryptococcal immune reconstitution inflammatory syndrome in an HIV-infected patient after anti-retroviral therapy: a case report. Ann Clin Microbiol Antimicrob 12: 40. doi: 10.1186/1476-0711-12-40 24354779

19. Jhamb R, Kashyap B, Das S, Berry N, Garg A (2014) Symptomatic relapse of HIV-associated cryptococcal meningitis: recurrent cryptococcal meningitis or Cryptococcus-related immune reconstitution inflammatory syndrome? Int J STD AIDS 25: 369–372. doi: 10.1177/0956462413506889 24108453

20. Naranbhai V, Chang CC, Durgiah R, Omarjee S, Lim A, et al. (2014) Compartmentalization of innate immune responses in the central nervous system during cryptococcal meningitis/HIV coinfection. AIDS.

21. Sun HY, Singh N (2011) Opportunistic infection-associated immune reconstitution syndrome in transplant recipients. Clin Infect Dis 53: 168–176. doi: 10.1093/cid/cir276 21690625

22. Zonios DI, Falloon J, Huang CY, Chaitt D, Bennett JE (2007) Cryptococcosis and idiopathic CD4 lymphocytopenia. Medicine (Baltimore) 86: 78–92. 17435588

23. Hagen F, Khayhan K, Theelen B, Kolecka A, Polacheck I, et al. (2015) Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol.

24. Harris JR, Lockhart SR, Debess E, Marsden-Haug N, Goldoft M, et al. (2011) Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis 53: 1188–1195. doi: 10.1093/cid/cir723 22016503

25. Rosen LB, Freeman AF, Yang LM, Jutivorakool K, Olivier KN, et al. (2013) Anti-GM-CSF Autoantibodies in Patients with Cryptococcal Meningitis. J Immunol 190: 3959–3966. doi: 10.4049/jimmunol.1202526 23509356

26. Han S, Lin YC, Wu T, Salgado AD, Mexhitaj I, et al. (2014) Comprehensive immunophenotyping of cerebrospinal fluid cells in patients with neuroimmunological diseases. J Immunol 192: 2551–2563. doi: 10.4049/jimmunol.1302884 24510966

27. Gaiottino J, Norgren N, Dobson R, Topping J, Nissim A, et al. (2013) Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 8: e75091. doi: 10.1371/journal.pone.0075091 24073237

28. Kuhle J, Plattner K, Bestwick JP, Lindberg RL, Ramagopalan SV, et al. (2013) A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler 19: 1597–1603. doi: 10.1177/1352458513482374 23529999

29. Bielekova B, McDermott M (2015) Will cerebrospinal fluid biomarkers guide future therapeutic decisions in multiple sclerosis? Neurology.

30. Ifergan I, Kebir H, Alvarez JI, Marceau G, Bernard M, et al. (2011) Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on alpha4 integrin. Brain 134: 3560–3577. doi: 10.1093/brain/awr268 22058139

31. Wuest SC, Edwan JH, Martin JF, Han S, Perry JS, et al. (2011) A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med 17: 604–609. doi: 10.1038/nm.2365 21532597

32. Wozniak KL, Levitz SM (2009) Isolation and purification of antigenic components of Cryptococcus. Methods Mol Biol 470: 71–83. doi: 10.1007/978-1-59745-204-5_7 19089377

33. Levitz SM, Specht CA (2006) The molecular basis for the immunogenicity of Cryptococcus neoformans mannoproteins. FEMS Yeast Res 6: 513–524. 16696647

34. Mansour MK, Yauch LE, Rottman JB, Levitz SM (2004) Protective efficacy of antigenic fractions in mouse models of cryptococcosis. Infect Immun 72: 1746–1754. 14977983

35. Specht CA, Nong S, Dan JM, Lee CK, Levitz SM (2007) Contribution of glycosylation to T cell responses stimulated by recombinant Cryptococcus neoformans mannoprotein. J Infect Dis 196: 796–800. 17674324

36. Chaturvedi AK, Hameed RS, Wozniak KL, Hole CR, Leopold Wager CM, et al. (2014) Vaccine-mediated immune responses to experimental pulmonary Cryptococcus gattii infection in mice. PLoS One 9: e104316. doi: 10.1371/journal.pone.0104316 25119981

37. Roy RM, Klein BS (2012) Dendritic cells in antifungal immunity and vaccine design. Cell Host Microbe 11: 436–446. doi: 10.1016/j.chom.2012.04.005 22607797

38. Poli V, Cortese R (1989) Interleukin 6 induces a liver-specific nuclear protein that binds to the promoter of acute-phase genes. Proc Natl Acad Sci U S A 86: 8202–8206. 2479021

39. Huffnagle GB, Yates JL, Lipscomb MF (1991) Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells. J Exp Med 173: 793–800. 1672543

40. Arora S, Hernandez Y, Erb-Downward JR, McDonald RA, Toews GB, et al. (2005) Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis. J Immunol 174: 6346–6356. 15879135

41. Hernandez Y, Arora S, Erb-Downward JR, McDonald RA, Toews GB, et al. (2005) Distinct roles for IL-4 and IL-10 in regulating T2 immunity during allergic bronchopulmonary mycosis. J Immunol 174: 1027–1036. 15634927

42. Hardison SE, Wozniak KL, Kolls JK, Wormley FL Jr. (2010) Interleukin-17 is not required for classical macrophage activation in a pulmonary mouse model of Cryptococcus neoformans infection. Infect Immun 78: 5341–5351. doi: 10.1128/IAI.00845-10 20921149

43. Wozniak KL, Hardison SE, Kolls JK, Wormley FL (2011) Role of IL-17A on resolution of pulmonary C. neoformans infection. PLoS One 6: e17204. doi: 10.1371/journal.pone.0017204 21359196

44. Olszewski MA, Zhang Y, Huffnagle GB (2010) Mechanisms of cryptococcal virulence and persistence. Future Microbiol 5: 1269–1288. doi: 10.2217/fmb.10.93 20722603

45. Singh N, Lortholary O, Alexander BD, Gupta KL, John GT, et al. (2005) An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis 40: 1756–1761. 15909263

46. Angkasekwinai P, Sringkarin N, Supasorn O, Fungkrajai M, Wang YH, et al. (2014) Cryptococcus gattii Infection Dampens Th1 and Th17 Responses by Attenuating Dendritic Cell Function and Pulmonary Chemokine Expression in the Immunocompetent Hosts. Infect Immun 82: 3880–3890. doi: 10.1128/IAI.01773-14 24980974

47. Haddow LJ, Colebunders R, Meintjes G, Lawn SD, Elliott JH, et al. (2010) Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 10: 791–802. doi: 10.1016/S1473-3099(10)70170-5 21029993

48. Chang CC, Omarjee S, Lim A, Spelman T, Gosnell BI, et al. (2013) Chemokine levels and chemokine receptor expression in the blood and the cerebrospinal fluid of HIV-infected patients with cryptococcal meningitis and cryptococcosis-associated immune reconstitution inflammatory syndrome. J Infect Dis 208: 1604–1612. doi: 10.1093/infdis/jit388 23908492

49. Boulware DR, Bonham SC, Meya DB, Wiesner DL, Park GS, et al. (2010) Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis 202: 962–970. doi: 10.1086/655785 20677939

50. Boulware DR, Meya DB, Bergemann TL, Wiesner DL, Rhein J, et al. (2010) Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 7: e1000384. doi: 10.1371/journal.pmed.1000384 21253011

51. Chang CC, Lim A, Omarjee S, Levitz SM, Gosnell BI, et al. (2013) Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-gamma responses before antiretroviral therapy but not higher T-cell responses during therapy. J Infect Dis 208: 898–906. doi: 10.1093/infdis/jit271 23766525

52. Arora S, Olszewski MA, Tsang TM, McDonald RA, Toews GB, et al. (2011) Effect of cytokine interplay on macrophage polarization during chronic pulmonary infection with Cryptococcus neoformans. Infect Immun 79: 1915–1926. doi: 10.1128/IAI.01270-10 21383052

53. Gabrysova L, Howes A, Saraiva M, O'Garra A (2014) The regulation of IL-10 expression. Curr Top Microbiol Immunol 380: 157–190. doi: 10.1007/978-3-662-43492-5_8 25004818

54. Herring AC, Lee J, McDonald RA, Toews GB, Huffnagle GB (2002) Induction of interleukin-12 and gamma interferon requires tumor necrosis factor alpha for protective T1-cell-mediated immunity to pulmonary Cryptococcus neoformans infection. Infect Immun 70: 2959–2964. 12010985

55. Huffnagle GB, Toews GB, Burdick MD, Boyd MB, McAllister KS, et al. (1996) Afferent phase production of TNF-alpha is required for the development of protective T cell immunity to Cryptococcus neoformans. J Immunol 157: 4529–4536. 8906831

56. Yauch LE, Lam JS, Levitz SM (2006) Direct inhibition of T-cell responses by the Cryptococcus capsular polysaccharide glucuronoxylomannan. PLoS Pathog 2: e120. 17096589

57. McQuiston TJ, Williamson PR (2012) Paradoxical roles of alveolar macrophages in the host response to Cryptococcus neoformans. J Infect Chemother 18: 1–9. doi: 10.1007/s10156-011-0306-2 22045161

58. Ponton J, Omaetxebarria MJ, Elguezabal N, Alvarez M, Moragues MD (2001) Immunoreactivity of the fungal cell wall. Med Mycol 39 Suppl 1: 101–110. 11800264

59. Davis J, Zheng WY, Glatman-Freedman A, Ng JA, Pagcatipunan MR, et al. (2007) Serologic evidence for regional differences in pediatric cryptococcal infection. Pediatr Infect Dis J 26: 549–551. 17529880

60. Saijo T, Chen J, Chen SC, Rosen LB, Yi J, et al. (2014) Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. MBio 5: e00912–00914. doi: 10.1128/mBio.00912-14 24643864

61. Del Poeta M (2004) Role of phagocytosis in the virulence of Cryptococcus neoformans. Eukaryot Cell 3: 1067–1075. 15470235

62. Liu L, Wakamatsu K, Ito S, Williamson PR (1999) Catecholamine oxidative products, but not melanin, are produced by Cryptococcus neoformans during neuropathogenesis in mice. Infect Immun 67: 108–112. 9864203

63. Blackstock R (2003) Roles for CD40, B7 and major histocompatibility complex in induction of enhanced immunity by cryptococcal polysaccharide-pulsed antigen-presenting cells. Immunology 108: 158–166. 12562324

64. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, et al. (2008) Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46: 1813–1821. doi: 10.1086/588660 18462102

65. Jaguin M, Houlbert N, Fardel O, Lecureur V (2013) Polarization profiles of human M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol 281: 51–61. doi: 10.1016/j.cellimm.2013.01.010 23454681

66. Hagen F, Vreuls W, Wouters M, Hendriks MJ, JF M (2014) Cryptococcus gattii infections in the Netherlands—a retrospective molecular diagnostic study using formalin fixed paraffin embedded pulmonary coin lesions. Mycoses 57 103.

67. Veron V, Simon S, Blanchet D, Aznar C (2009) Real-time polymerase chain reaction detection of Cryptococcus neoformans and Cryptococcus gattii in human samples. Diagn Microbiol Infect Dis 65: 69–72. doi: 10.1016/j.diagmicrobio.2009.05.005 19679239

68. Dunn OJ (1961) Multiple Comparisons among Means. Journal of the American Statistical Association 56: 52–64.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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