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Current Fungal Infection Reports

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01-12-2019 | Candidiasis | Epidemiology of Fungal Infections (T Chiller and J Baddley, Section Editors)

Genetic Variation and Fungal Infection Risk: State of the Art

Author: Michail S. Lionakis

Published in: Current Fungal Infection Reports | Issue 4/2019

Abstract

Purpose of Review

Fungal infections cause significant mortality in patients with acquired immunodeficiencies including AIDS, hematological malignancies, transplantation, and receipt of corticosteroids, biologics or small-molecule kinase inhibitors that impair key immune pathways. The contribution of several such pathways in antifungal immunity has been uncovered by inherited immunodeficiencies featuring profound fungal susceptibility. Furthermore, the risk of fungal infection in patients with acquired immunodeficiencies may be modulated by single nucleotide polymorphisms (SNPs) in immune-related genes. This review outlines key features underlying human genetic fungal infection predisposition.

Recent Findings

The discovery of monogenic disorders that cause fungal disease and the characterization of immune-related gene SNPs that may regulate fungal susceptibility have provided important insights into how genetic variation affects development and outcome of fungal infections in humans.

Summary

Recognition of individualized genetic fungal susceptibility traits in humans should help devise precision-medicine strategies for risk assessment, prognostication, and treatment of patients with opportunistic fungal infections.

Robert VA, Casadevall A. Vertebrate endothermy restricts most fungi as potential pathogens. J Infect Dis. 2009;200(10):1623–6. https://doi.org/10.1086/644642.CrossRefPubMed

Lionakis MS, Iliev ID, Hohl TM. Immunity against fungi. JCI Insight. 2017;2(11). doi:10.1172/jci.insight.93156.

Lionakis MS, Levitz SM. Host control of fungal infections: lessons from basic studies and human cohorts. Annu Rev Immunol. 2018;36:157–91. https://doi.org/10.1146/annurev-immunol-042617-053318.CrossRefPubMed

Arvanitis M, Anagnostou T, Fuchs BB, Caliendo AM, Mylonakis E. Molecular and nonmolecular diagnostic methods for invasive fungal infections. Clin Microbiol Rev. 2014;27(3):490–526. https://doi.org/10.1128/CMR.00091-13.CrossRefPubMedPubMedCentral

McCarthy MW, Kontoyiannis DP, Cornely OA, Perfect JR, Walsh TJ. Novel agents and drug targets to meet the challenges of resistant fungi. J Infect Dis. 2017;216(suppl_3):S474-S83. doi:10.1093/infdis/jix130.CrossRef

Lionakis MS. Genetic susceptibility to fungal infections in humans. Curr Fungal Infect Rep. 2012;6(1):11–22. https://doi.org/10.1007/s12281-011-0076-4.CrossRefPubMed

Lionakis MS, Netea MG, Holland SM. Mendelian genetics of human susceptibility to fungal infection. Cold Spring Harb Perspect Med. 2014;4(6). doi:10.1101/cshperspect.a019638.CrossRef

Puel A, Cypowyj S, Marodi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol. 2012;12(6):616–22. https://doi.org/10.1097/ACI.0b013e328358cc0b.CrossRefPubMedPubMedCentral

•• Conti HR, Bruno VM, Childs EE, Daugherty S, Hunter JP, Mengesha BG et al. IL-17 Receptor signaling in oral epithelial cells is critical for protection against oropharyngeal candidiasis. Cell Host Microbe. 2016;20(5):606-617. doi:https://doi.org/10.1016/j.chom.2016.10.001. This paper describes the critical contribution of epithelial cell IL-17 receptor expression in host defense against mucosal candidiasis, via the induction of anti-Candidaantimicrobial peptides such as beta-defensin 3.CrossRef

10.

Conti HR, Peterson AC, Brane L, Huppler AR, Hernandez-Santos N, Whibley N, et al. Oral-resident natural Th17 cells and gammadelta T cells control opportunistic Candida albicans infections. J Exp Med. 2014;211(10):2075–84. https://doi.org/10.1084/jem.20130877.CrossRefPubMedPubMedCentral

11.

Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206(2):299–311. https://doi.org/10.1084/jem.20081463.CrossRefPubMedPubMedCentral

12.

Sparber F, Dolowschiak T, Mertens S, Lauener L, Clausen BE, Joller N, et al. Langerin+ DCs regulate innate IL-17 production in the oral mucosa during Candida albicans-mediated infection. PLoS Pathog. 2018;14(5):e1007069. https://doi.org/10.1371/journal.ppat.1007069.CrossRefPubMedPubMedCentral

13.

Trautwein-Weidner K, Gladiator A, Kirchner FR, Becattini S, Rulicke T, Sallusto F, et al. Antigen-specific Th17 cells are primed by distinct and complementary dendritic cell subsets in oropharyngeal candidiasis. PLoS Pathog. 2015;11(10):e1005164. https://doi.org/10.1371/journal.ppat.1005164.CrossRefPubMedPubMedCentral

14.

Jiang L, Fang M, Tao R, Yong X, Wu T. Recombinant human interleukin 17A enhances the anti-Candida effect of human oral mucosal epithelial cells by inhibiting Candida albicans growth and inducing antimicrobial peptides secretion. J Oral Pathol Med. 2019. https://doi.org/10.1111/jop.12889.

15.

Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332(6025):65–8. https://doi.org/10.1126/science.1200439.CrossRefPubMedPubMedCentral

16.

Boisson B, Wang C, Pedergnana V, Wu L, Cypowyj S, Rybojad M, et al. An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity. 2013;39(4):676–86. https://doi.org/10.1016/j.immuni.2013.09.002.CrossRefPubMed

17.

Ling Y, Cypowyj S, Aytekin C, Galicchio M, Camcioglu Y, Nepesov S, et al. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J Exp Med. 2015;212(5):619–31. https://doi.org/10.1084/jem.20141065.CrossRefPubMedPubMedCentral

18.

•• Levy R, Okada S, Beziat V, Moriya K, Liu C, Chai LY, et al. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency. Proc Natl Acad Sci U S A. 2016;113(51):E8277–E85. https://doi.org/10.1073/pnas.1618300114This paper provides a systematic overview of the clinical, genetic and immunological features in patients with inherited deficiency in IL-17RA. CrossRefPubMedPubMedCentral

19.

Lionakis MS. New insights into innate immune control of systemic candidiasis. Med Mycol. 2014;52(6):555–64. https://doi.org/10.1093/mmy/myu029.CrossRefPubMedPubMedCentral

20.

Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, et al. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science. 2015;349(6248):606–13. https://doi.org/10.1126/science.aaa4282.CrossRefPubMedPubMedCentral

21.

Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452(7188):773–6. https://doi.org/10.1038/nature06764.CrossRefPubMedPubMedCentral

22.

Drummond RA, Franco LM, Lionakis MS. Human CARD9: a critical molecule of fungal immune surveillance. Front Immunol. 2018a;9:1836. https://doi.org/10.3389/fimmu.2018.01836.CrossRefPubMedPubMedCentral

23.

Tangye SG, Pillay B, Randall KL, Avery DT, Phan TG, Gray P, et al. Dedicator of cytokinesis 8-deficient CD4(+) T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells. J Allergy Clin Immunol. 2017;139(3):933–49. https://doi.org/10.1016/j.jaci.2016.07.016.CrossRefPubMed

24.

Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48. https://doi.org/10.1084/jem.20110958.CrossRefPubMedPubMedCentral

25.

Constantine GM, Lionakis MS. Lessons from primary immunodeficiencies: autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Immunol Rev. 2019;287(1):103–20. https://doi.org/10.1111/imr.12714.CrossRefPubMed

26.

Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207(2):291–7. https://doi.org/10.1084/jem.20091983.CrossRefPubMedPubMedCentral

27.

Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010;207(2):299–308. https://doi.org/10.1084/jem.20091669.CrossRefPubMedPubMedCentral

28.

Saunte DM, Mrowietz U, Puig L, Zachariae C. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management. Br J Dermatol. 2017;177(1):47–62. https://doi.org/10.1111/bjd.15015.CrossRefPubMed

29.

Netea MG, Joosten LA, van der Meer JW, Kullberg BJ, van de Veerdonk FL. Immune defence against Candida fungal infections. Nat Rev Immunol. 2015;15(10):630–42. https://doi.org/10.1038/nri3897.CrossRefPubMed

30.

Lehrer RI, Cline MJ. Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection. J Clin Invest. 1969;48(8):1478–88. https://doi.org/10.1172/JCI106114.CrossRefPubMedPubMedCentral

31.

Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000;79(3):155–69.CrossRef

32.

Drummond RA, Collar AL, Swamydas M, Rodriguez CA, Lim JK, Mendez LM, et al. CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. PLoS Pathog. 2015;11(12):e1005293. https://doi.org/10.1371/journal.ppat.1005293.CrossRefPubMedPubMedCentral

33.

Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361(18):1727–35. https://doi.org/10.1056/NEJMoa0810719.CrossRefPubMedPubMedCentral

34.

Lanternier F, Mahdaviani SA, Barbati E, Chaussade H, Koumar Y, Levy R, et al. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. J Allergy Clin Immunol. 2015a;135(6):1558–68 e2. https://doi.org/10.1016/j.jaci.2014.12.1930.CrossRefPubMedPubMedCentral

35.

• Corvilain E, Casanova JL, Puel A. Inherited CARD9 deficiency: invasive disease caused by ascomycete fungi in previously healthy children and adults. J Clin Immunol. 2018;38(6):656–93. https://doi.org/10.1007/s10875-018-0539-2This is a thorough review related to fungal disease susceptibility in CARD9-deficient patients. CrossRefPubMedPubMedCentral

36.

Li J, Vinh DC, Casanova JL, Puel A. Inborn errors of immunity underlying fungal diseases in otherwise healthy individuals. Curr Opin Microbiol. 2017;40:46–57. https://doi.org/10.1016/j.mib.2017.10.016.CrossRefPubMedPubMedCentral

37.

•• Drummond RA, Swamydas M, Oikonomou V, Zhai B, Dambuza IM, Schaefer BC, et al. CARD9(+) microglia promote antifungal immunity via IL-1beta- and CXCL1-mediated neutrophil recruitment. Nat Immunol. 2019;20(5):559–70. https://doi.org/10.1038/s41590-019-0377-2This paper outlines an intricate network of microglial-fungal interactions in theCandida-infected central nervous system that promote CARD9-dependent protective neutrophil recruitment.CrossRefPubMedPubMedCentral

38.

Moyes DL, Wilson D, Richardson JP, Mogavero S, Tang SX, Wernecke J, et al. Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature. 2016;532(7597):64–8. https://doi.org/10.1038/nature17625.CrossRefPubMedPubMedCentral

39.

Swidergall M, Solis NV, Wang Z, Phan QT, Marshall ME, Lionakis MS, et al. EphA2 Is a neutrophil receptor for Candida albicans that stimulates antifungal activity during oropharyngeal infection. Cell Rep. 2019;28(2):423–33 e5. https://doi.org/10.1016/j.celrep.2019.06.020.CrossRefPubMedPubMedCentral

40.

Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121(13):2385–92. https://doi.org/10.1182/blood-2012-08-450551.CrossRefPubMed

41.

• Drummond RA, Zahra FT, Natarajan M, Swamydas M, Hsu AP, Wheat LJ, et al. GM-CSF therapy in human caspase recruitment domain-containing protein 9 deficiency. J Allergy Clin Immunol. 2018b;142(4):1334–8 e5. https://doi.org/10.1016/j.jaci.2018.05.025This paper along with the paper of Gavino et al outline differential outcomes of GM-CSF immunotherapy in CARD9-deficient patients with brain fungal disease. CrossRefPubMed

42.

Gavino C, Cotter A, Lichtenstein D, Lejtenyi D, Fortin C, Legault C, et al. CARD9 deficiency and spontaneous central nervous system candidiasis: complete clinical remission with GM-CSF therapy. Clin Infect Dis. 2014;59(1):81–4. https://doi.org/10.1093/cid/ciu215.CrossRefPubMedPubMedCentral

43.

• Gavino C, Hamel N, Zeng JB, Legault C, Guiot MC, Chankowsky J, et al. Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. J Allergy Clin Immunol. 2016;137(4):1178–88 e1-7. https://doi.org/10.1016/j.jaci.2015.09.016This paper along with the paper of Drummond et al outline differential outcomes of GM-CSF immunotherapy in CARD9-deficient patients with brain fungal disease. CrossRefPubMed

44.

• Queiroz-Telles F, Mercier T, Maertens J, Sola CBS, Bonfim C, Lortholary O, et al. Successful allogenic stem cell transplantation in patients with inherited CARD9 deficiency. J Clin Immunol. 2019. https://doi.org/10.1007/s10875-019-00662-z.This paper describes the first successful allogeneic hematopoietic stem cell transplants in CARD9-deficient patients with refractory subcutaneous fungal disease. CrossRef

45.

Drummond RA, Lionakis MS. Mechanistic insights into the role of C-type lectin receptor/CARD9 signaling in human antifungal immunity. Front Cell Infect Microbiol. 2016;6:39. https://doi.org/10.3389/fcimb.2016.00039.CrossRefPubMedPubMedCentral

46.

Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006;442(7103):651–6. https://doi.org/10.1038/nature04926.CrossRefPubMed

47.

Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol. 2017;10(1):145–7. https://doi.org/10.1186/s13045-017-0512-1.CrossRefPubMedPubMedCentral

48.

Lanternier F, Barbati E, Meinzer U, Liu L, Pedergnana V, Migaud M, et al. Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection. J Infect Dis. 2015b;211(8):1241–50. https://doi.org/10.1093/infdis/jiu412.CrossRefPubMed

49.

Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, Prando C, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med. 2013;369(18):1704–14. https://doi.org/10.1056/NEJMoa1208487.CrossRefPubMedPubMedCentral

50.

• De Bruyne M, Hoste L, Bogaert DJ, Van den Bossche L, Tavernier SJ, Parthoens E, et al. A CARD9 founder mutation disrupts NF-kappaB signaling by inhibiting BCL10 and MALT1 recruitment and signalosome formation. Front Immunol. 2018;9:2366. https://doi.org/10.3389/fimmu.2018.02366This paper together with that by Rieber et al showed that CARD9-deficient patients are at risk of developing extrapulmonary aspergillosis that spares the lungs.CrossRefPubMedPubMedCentral

51.

• Rieber N, Gazendam RP, Freeman AF, Hsu AP, Collar AL, Sugui JA, et al. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI Insight. 2016;1(17):e89890–10.1172/jci.insight.89890 This paper together with that by De Bruyne et al showed that CARD9-deficient patients are at risk of developing extrapulmonary aspergillosis that spares the lungs.CrossRef

52.

Hohl TM. Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities. Curr Opin Infect Dis. 2017. https://doi.org/10.1097/QCO.0000000000000381.CrossRef

53.

Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). 2000;79(3):170–200.CrossRef

54.

Seyedmousavi S, Lionakis MS, Parta M, Peterson SW, Kwon-Chung KJ. Emerging Aspergillus species almost exclusively associated with primary immunodeficiencies. Open Forum Infect Dis. 2018;5(9):ofy213. https://doi.org/10.1093/ofid/ofy213.CrossRefPubMedPubMedCentral

55.

•• van de Geer A, Nieto-Patlan A, Kuhns DB, Tool AT, Arias AA, Bouaziz M, et al. Inherited p40phox deficiency differs from classic chronic granulomatous disease. J Clin Invest. 2018;128(9):3957–75. https://doi.org/10.1172/JCI97116This paper outlines critical clinical and immunological differences in patients with chronic granulomatous disease caused by deficiency of the p40phox subunit of the NADPH oxidase complex. CrossRefPubMedPubMedCentral

56.

Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363(27):2600–10. https://doi.org/10.1056/NEJMoa1007097.CrossRefPubMedPubMedCentral

57.

Vinh DC, Sugui JA, Hsu AP, Freeman AF, Holland SM. Invasive fungal disease in autosomal-dominant hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125(6):1389–90. https://doi.org/10.1016/j.jaci.2010.01.047.CrossRefPubMedPubMedCentral

58.

• Khourieh J, Rao G, Habib T, Avery DT, Lefevre-Utile A, Chandesris MO, et al. A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance. Proc Natl Acad Sci U S A. 2019. https://doi.org/10.1073/pnas.1901409116This paper shows that deep intronic splice mutations can exert dominant-negative effects and manifest with hyper-IgE (Job's) syndrome.CrossRef

59.

Natarajan M, Hsu AP, Weinreich MA, Zhang Y, Niemela JE, Butman JA, et al. Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency. J Allergy Clin Immunol. 2018;142(3):993–7 e3. https://doi.org/10.1016/j.jaci.2018.05.009.CrossRefPubMed

60.

•• Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017. https://doi.org/10.1016/j.ccell.2017.04.012This paper revealed an unexpected susceptiblity of ibrutinib-treated patients to invasive aspergillosis and showed that, surprisingly, Btk-deficient mice are also susceptible to pulmonaryAspergillusinfection.CrossRef

61.

Zarakas MADJ, Chamilos G, Lionakis MS. Fungal infections with ibrutinib and other small-molecule kinase inhibitors. Curr Fungal Infect Rep. 2019;13:86–98. https://doi.org/10.1007/s12281-019-00343-9.CrossRefPubMed

62.

Chamilos G, Lionakis MS, Kontoyiannis DP. Call for action: invasive fungal infections associated with ibrutinib and other small molecule kinase inhibitors targeting immune signaling pathways. Clin Infect Dis. 2018;66(1):140–8. https://doi.org/10.1093/cid/cix687.CrossRefPubMed

63.

Ghez D, Calleja A, Protin C, Baron M, Ledoux MP, Damaj G, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131(17):1955–9. https://doi.org/10.1182/blood-2017-11-818286.CrossRefPubMed

64.

Varughese T, Taur Y, Cohen N, Palomba ML, Seo SK, Hohl TM, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67(5):687–92. https://doi.org/10.1093/cid/ciy175.CrossRefPubMedPubMedCentral

65.

• Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Ibrutinib blocks Btk-dependent NF-kB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Blood. 2018;132(18):1985–8. https://doi.org/10.1182/blood-2017-12-823393This work defined defects in innate signaling of human macrophages upon ibrutinib exposure that affects uptake ofAspergillus. CrossRefPubMedPubMedCentral

66.

Glotz D, Russ G, Rostaing L, Legendre C, Tufveson G, Chadban S, et al. Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies. Am J Transplant. 2019. https://doi.org/10.1111/ajt.15397.CrossRef

67.

Socie G, Caby-Tosi MP, Marantz JL, Cole A, Bedrosian CL, Gasteyger C, et al. Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis. Br J Haematol. 2019;185(2):297–310. https://doi.org/10.1111/bjh.15790.CrossRefPubMedPubMedCentral

68.

• Merkhofer RM, Jr., O'Neill MB, Xiong D, Hernandez-Santos N, Dobson H, Fites JS et al. Investigation of genetic susceptibility to blastomycosis reveals interleukin-6 as a potential susceptibility locus. MBio. 2019;10(3). doi:https://doi.org/10.1128/mBio.01224-19. This paper employed whole genome sequencing and showed that susceptibility to blastomycosis in individuals of Hmong ancestry in Wisconsin is associated with genetic variants surrounding theIL6locus.

69.

Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med. 2012;367(8):725–34. https://doi.org/10.1056/NEJMoa1111160.CrossRefPubMedPubMedCentral

70.

Saijo T, Chen J, Chen SC, Rosen LB, Yi J, Sorrell TC, et al. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. MBio. 2014;5(2):e00912–4. https://doi.org/10.1128/mBio.00912-14.CrossRefPubMedPubMedCentral

71.

Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Primers. 2018;4:18026. https://doi.org/10.1038/nrdp.2018.26.CrossRefPubMed

72.

Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet. 2003;362(9398):1828–38. https://doi.org/10.1016/S0140-6736(03)14904-5.CrossRefPubMed

73.

Segal BH. Aspergillosis. N Engl J Med. 2009;360(18):1870–84. https://doi.org/10.1056/NEJMra0808853.CrossRefPubMed

74.

Cunha C, Carvalho A. Genetic defects in fungal recognition and susceptibility to invasive pulmonary aspergillosis. Med Mycol. 2019;57(Supplement_2):S211–S8. https://doi.org/10.1093/mmy/myy057.CrossRefPubMed

75.

Khanna N, Stuehler C, Lunemann A, Wojtowicz A, Bochud PY, Leibundgut-Landmann S. Host response to fungal infections - how immunology and host genetics could help to identify and treat patients at risk. Swiss Med Wkly. 2016;146:w14350. https://doi.org/10.4414/smw.2016.14350.CrossRefPubMed

76.

Wojtowicz A, Bochud PY. Host genetics of invasive Aspergillus and Candida infections. Semin Immunopathol. 2015;37(2):173–86. https://doi.org/10.1007/s00281-014-0468-y.CrossRefPubMed

77.

Johnson MD, Plantinga TS, van de Vosse E, Velez Edwards DR, Smith PB, Alexander BD, et al. Cytokine gene polymorphisms and the outcome of invasive candidiasis: a prospective cohort study. Clin Infect Dis. 2012;54(4):502–10. https://doi.org/10.1093/cid/cir827.CrossRefPubMed

78.

Kumar V, Cheng SC, Johnson MD, Smeekens SP, Wojtowicz A, Giamarellos-Bourboulis E, et al. Immunochip SNP array identifies novel genetic variants conferring susceptibility to candidaemia. Nat Commun. 2014;5:4675. https://doi.org/10.1038/ncomms5675.CrossRefPubMedPubMedCentral

79.

Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD, Jaeger M, et al. CX3CR1-dependent renal macrophage survival promotes Candida control and host survival. J Clin Invest. 2013;123(12):5035–51. https://doi.org/10.1172/JCI71307.CrossRefPubMedPubMedCentral

80.

Plantinga TS, Johnson MD, Scott WK, van de Vosse E, Velez Edwards DR, Smith PB, et al. Toll-like receptor 1 polymorphisms increase susceptibility to candidemia. J Infect Dis. 2012;205(6):934–43. https://doi.org/10.1093/infdis/jir867.CrossRefPubMedPubMedCentral

81.

Roth S, Bergmann H, Jaeger M, Yeroslaviz A, Neumann K, Koenig PA, et al. Vav proteins are key regulators of Card9 signaling for innate antifungal immunity. Cell Rep. 2016;17(10):2572–83. https://doi.org/10.1016/j.celrep.2016.11.018.CrossRefPubMedPubMedCentral

82.

Smeekens SP, Ng A, Kumar V, Johnson MD, Plantinga TS, van Diemen C, et al. Functional genomics identifies type I interferon pathway as central for host defense against Candida albicans. Nat Commun. 2013;4:1342. https://doi.org/10.1038/ncomms2343.CrossRefPubMedPubMedCentral

83.

• Swamydas M, Gao JL, Break TJ, Johnson MD, Jaeger M, Rodriguez CA, et al. CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival. Sci Transl Med. 2016;8(322):322ra10. https://doi.org/10.1126/scitranslmed.aac7718This paper revealed the first function of Cxcr1 in mice and identified this chemokine receptor as a critical mediator of neutrophil function againstCandidain both mice and humans.CrossRefPubMedPubMedCentral

84.

Wojtowicz A, Tissot F, Lamoth F, Orasch C, Eggimann P, Siegemund M, et al. Polymorphisms in tumor necrosis factor-alpha increase susceptibility to intra-abdominal Candida infection in high-risk surgical ICU patients*. Crit Care Med. 2014;42(4):e304–8. https://doi.org/10.1097/CCM.0000000000000208.CrossRefPubMed

85.

Collar AL, Swamydas M, O'Hayre M, Sajib MS, Hoffman KW, Singh SP, et al. The homozygous CX3CR1-M280 mutation impairs human monocyte survival. JCI Insight. 2018;3(3). https://doi.org/10.1172/jci.insight.95417.

86.

Break TJ, Jaeger M, Solis NV, Filler SG, Rodriguez CA, Lim JK, et al. CX3CR1 is dispensable for control of mucosal Candida albicans infections in mice and humans. Infect Immun. 2015;83(3):958–65. https://doi.org/10.1128/IAI.02604-14.CrossRefPubMedPubMedCentral

87.

Cunha C, Aversa F, Lacerda JF, Busca A, Kurzai O, Grube M, et al. Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med. 2014;370(5):421–32. https://doi.org/10.1056/NEJMoa1211161.CrossRefPubMed

88.

•• Fisher CE, Hohl TM, Fan W, Storer BE, Levine DM, Zhao LP, et al. Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation. Blood. 2017;129(19):2693–701. https://doi.org/10.1182/blood-2016-10-743294This paper evaluated a large number of transplant recipients with or without aspergillosis and validated several single nucleotide polymorphisms as modulators of aspergillosis risk in these patients. CrossRefPubMedPubMedCentral

89.

Gresnigt MS, Cunha C, Jaeger M, Goncalves SM, Malireddi RKS, Ammerdorffer A, et al. Genetic deficiency of NOD2 confers resistance to invasive aspergillosis. Nat Commun. 2018;9(1):2636. https://doi.org/10.1038/s41467-018-04912-3.CrossRefPubMedPubMedCentral

90.

Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359(17):1766–77. https://doi.org/10.1056/NEJMoa0802629.CrossRefPubMedPubMedCentral

91.

Mezger M, Steffens M, Beyer M, Manger C, Eberle J, Toliat MR, et al. Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood. 2008;111(2):534–6. https://doi.org/10.1182/blood-2007-05-090928.CrossRefPubMed

92.

•• Stappers MHT, Clark AE, Aimanianda V, Bidula S, Reid DM, Asamaphan P, et al. Recognition of DHN-melanin by a C-type lectin receptor is required for immunity to Aspergillus. Nature. 2018;555(7696):382–6. https://doi.org/10.1038/nature25974This paper discovered CLEC1A as a C-type lectin receptor important for the recognition of fungal melanin and revealed that genetic variation at this locus may influence the risk of human aspergillosis. CrossRefPubMedPubMedCentral

93.

Zaas AK, Liao G, Chien JW, Weinberg C, Shore D, Giles SS, et al. Plasminogen alleles influence susceptibility to invasive aspergillosis. PLoS Genet. 2008;4(6):e1000101. https://doi.org/10.1371/journal.pgen.1000101.CrossRefPubMedPubMedCentral

94.

Kesh S, Mensah NY, Peterlongo P, Jaffe D, Hsu K, Van Den Brink M, et al. TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Ann N Y Acad Sci. 2005;1062:95–103. https://doi.org/10.1196/annals.1358.012.CrossRefPubMed

95.

Sainz J, Salas-Alvarado I, Lopez-Fernandez E, Olmedo C, Comino A, Garcia F, et al. TNFR1 mRNA expression level and TNFR1 gene polymorphisms are predictive markers for susceptibility to develop invasive pulmonary aspergillosis. Int J Immunopathol Pharmacol. 2010;23(2):423–36. https://doi.org/10.1177/039463201002300205.CrossRefPubMed

96.

Cunha C, Di Ianni M, Bozza S, Giovannini G, Zagarella S, Zelante T, et al. Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood. 2010;116(24):5394–402. https://doi.org/10.1182/blood-2010-04-279307.CrossRefPubMed

97.

Garlanda C, Hirsch E, Bozza S, Salustri A, De Acetis M, Nota R, et al. Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature. 2002;420(6912):182–6. https://doi.org/10.1038/nature01195.CrossRefPubMed

98.

Cunha C, Monteiro AA, Oliveira-Coelho A, Kuhne J, Rodrigues F, Sasaki SD, et al. PTX3-based genetic testing for risk of aspergillosis after lung transplant. Clin Infect Dis. 2015;61(12):1893–4. https://doi.org/10.1093/cid/civ679.CrossRefPubMed

99.

He Q, Li H, Rui Y, Liu L, He B, Shi Y, et al. Pentraxin 3 gene polymorphisms and pulmonary aspergillosis in chronic obstructive pulmonary disease patients. Clin Infect Dis. 2018;66(2):261–7. https://doi.org/10.1093/cid/cix749.CrossRefPubMed

100.

Goncalves SM, Lagrou K, Rodrigues CS, Campos CF, Bernal-Martinez L, Rodrigues F, et al. Evaluation of bronchoalveolar lavage fluid cytokines as biomarkers for invasive pulmonary aspergillosis in at-risk patients. Front Microbiol. 2017;8:2362. https://doi.org/10.3389/fmicb.2017.02362.CrossRefPubMedPubMedCentral

101.

Marra E, Sousa VL, Gaziano R, Pacello ML, Arseni B, Aurisicchio L, et al. Efficacy of PTX3 and posaconazole combination in a rat model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2014;58(10):6284–6. https://doi.org/10.1128/AAC.03038-14.CrossRefPubMedPubMedCentral

Title: Genetic Variation and Fungal Infection Risk: State of the Art
Author: Michail S. Lionakis
Publication date: 01-12-2019
Publisher: Springer US
Keywords: Candidiasis
Candidiasis
Aspergillosis
Immunodeficiency
Invasive Aspergillosis
Published in: Current Fungal Infection Reports / Issue 4/2019
Print ISSN: 1936-3761
Electronic ISSN: 1936-377X
DOI: https://doi.org/10.1007/s12281-019-00362-6

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