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Pathogen–Host Interaction of Histoplasma capsulatum: an Update

  • Fungal Genomics and Pathogenesis (S Shoham, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Histoplasma capsulatum is a dimorphic fungus endemic to the Americas but is increasingly recognized as a global pathogen. In this review, we describe the most current findings in host evasion, host–pathogen interaction, therapeutics, and vaccines.

Recent Findings

Recent advances in the understanding of H. capsulatum virulence and immunity include the importance of host–pathogen nutrient modulation, immune cell transcriptional regulators, cytokine signaling, and coordination of innate and adaptive immunity.

Summary

The latest developments in our understanding of H. capsulatum infection lay the foundation for future clinical breakthroughs in prevention, diagnosis, and treatment of this intracellular fungal pathogen.

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References

  1. Chu JH, Feudtner C, Heydon K, Walsh TJ, Zaoutis TE. Hospitalizations for endemic mycoses: a population-based national study. Clin Infect Dis. 2006;42(6):822–5. doi:10.1086/500405.

    Article  PubMed  Google Scholar 

  2. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4(165), 165rv13.

    Article  PubMed  CAS  Google Scholar 

  3. Bohse ML, Woods JP. RNA interference-mediated silencing of the YPS3 gene of Histoplasma capsulatum reveals virulence defects. Infect Immun. 2007;75(6):2811–7. doi:10.1128/IAI.00304-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Teixeira Mde M, Patane JS, Taylor ML, Gomez BL, Theodoro RC, de Hoog S, et al. Worldwide phylogenetic distributions and population dynamics of the genus Histoplasma. PLoS Negl Trop Dis. 2016;10(6), e0004732. doi:10.1371/journal.pntd.0004732.

    Article  PubMed  Google Scholar 

  5. Rappleye CA, Eissenberg LG, Goldman WE. Histoplasma capsulatum alpha-(1,3)-glucan blocks innate immune recognition by the beta-glucan receptor. Proc Natl Acad Sci U S A. 2007;104(4):1366–70. doi:10.1073/pnas.0609848104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Garfoot AL, Shen Q, Wuthrich M, Klein BS, Rappleye CA. The Eng1 beta-glucanase enhances histoplasma virulence by reducing beta-glucan exposure. MBio. 2016;7(2). doi:10.1128/mBio.01388-15.

  7. Sepulveda VE, Williams CL, Goldman WE. Comparison of phylogenetically distinct Histoplasma strains reveals evolutionarily divergent virulence strategies. MBio. 2014;5(4):e01376–14. doi:10.1128/mBio.01376-14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Youseff BH, Holbrook ED, Smolnycki KA, Rappleye CA. Extracellular superoxide dismutase protects Histoplasma yeast cells from host-derived oxidative stress. PLoS Pathog. 2012;8(5), e1002713. doi:10.1371/journal.ppat.1002713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Holbrook ED, Smolnycki KA, Youseff BH, Rappleye CA. Redundant catalases detoxify phagocyte reactive oxygen and facilitate Histoplasma capsulatum pathogenesis. Infect Immun. 2013;81(7):2334–46. doi:10.1128/IAI.00173-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Newman SL, Gootee L, Brunner G, Deepe Jr GS. Chloroquine induces human macrophage killing of Histoplasma capsulatum by limiting the availability of intracellular iron and is therapeutic in a murine model of histoplasmosis. J Clin Invest. 1994;93(4):1422–9. doi:10.1172/JCI117119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Isaac DT, Coady A, Van Prooyen N, Sil A. The 3-hydroxy-methylglutaryl coenzyme A lyase HCL1 is required for macrophage colonization by human fungal pathogen Histoplasma capsulatum. Infect Immun. 2013;81(2):411–20. doi:10.1128/IAI.00833-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Newman SL, Gootee L, Hilty J, Morris RE. Human macrophages do not require phagosome acidification to mediate fungistatic/fungicidal activity against Histoplasma capsulatum. J Immunol. 2006;176(3):1806–13.

    Article  CAS  PubMed  Google Scholar 

  13. Gilmore SA, Voorhies M, Gebhart D, Sil A. Genome-wide reprogramming of transcript architecture by temperature specifies the developmental states of the human pathogen Histoplasma. PLoS Genet. 2015;11(7), e1005395. doi:10.1371/journal.pgen.1005395.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Newman SL, Lemen W, Smulian AG. Dendritic cells restrict the transformation of Histoplasma capsulatum conidia into yeasts. Med Mycol. 2011;49(4):356–64. doi:10.3109/13693786.2010.531295.

    Article  CAS  PubMed  Google Scholar 

  15. Deepe Jr GS, Buesing WR. Deciphering the pathways of death of Histoplasma capsulatum-infected macrophages: implications for the immunopathogenesis of early infection. J Immunol. 2012;188(1):334–44. doi:10.4049/jimmunol.1102175.

    Article  CAS  PubMed  Google Scholar 

  16. Pitangui Nde S, Sardi Jde C, Voltan AR, Dos Santos CT, da Silva JF, da Silva RA, et al. An intracellular arrangement of Histoplasma capsulatum yeast-aggregates generates nuclear damage to the cultured murine alveolar macrophages. Front Microbiol. 2015;6:1526. doi:10.3389/fmicb.2015.01526.

    PubMed  Google Scholar 

  17. Isaac DT, Berkes CA, English BC, Hocking Murray D, Lee YN, Coady A, et al. Macrophage cell death and transcriptional response are actively triggered by the fungal virulence factor Cbp1 during H. capsulatum infection. Mol Microbiol. 2015;98(5):910–29. doi:10.1111/mmi.13168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. DuBois JC, Pasula R, Dade JE, Smulian AG. Yeast transcriptome and in vivo hypoxia detection reveals Histoplasma capsulatum response to low oxygen tension. Med Mycol. 2016;54(1):40–58. doi:10.1093/mmy/myv073.

    PubMed  Google Scholar 

  19. Osborne TF. Sterols for oxygen: the metabolic burden of microbial SREBP. Mol Cell. 2011;44(2):172–4. doi:10.1016/j.molcel.2011.10.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dade J, DuBois JC, Pasula R, Donnell AM, Caruso JA, Smulian AG, et al. HcZrt2, a zinc responsive gene, is indispensable for the survival of Histoplasma capsulatum in vivo. Med Mycol. 2016. doi:10.1093/mmy/myw045.

    Google Scholar 

  21. Hoebe K, Janssen E, Beutler B. The interface between innate and adaptive immunity. Nat Immunol. 2004;5(10):971–4. doi:10.1038/ni1004-971.

    Article  CAS  PubMed  Google Scholar 

  22. Martin TR, Frevert CW. Innate immunity in the lungs. Proc Am Thorac Soc. 2005;2(5):403–11. doi:10.1513/pats.200508-090JS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Abram CL, Lowell CA. The ins and outs of leukocyte integrin signaling. Annu Rev Immunol. 2009;27:339–62. doi:10.1146/annurev.immunol.021908.132554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Newman SL, Gootee L. Colony-stimulating factors activate human macrophages to inhibit intracellular growth of Histoplasma capsulatum yeasts. Infect Immun. 1992;60(11):4593–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gildea LA, Gibbons R, Finkelman FD, Deepe Jr GS. Overexpression of interleukin-4 in lungs of mice impairs elimination of Histoplasma capsulatum. Infect Immun. 2003;71(7):3787–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Szymczak WA, Deepe Jr GS. The CCL7-CCL2-CCR2 axis regulates IL-4 production in lungs and fungal immunity. J Immunol. 2009;183(3):1964–74. doi:10.4049/jimmunol.0901316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cain JA, Deepe Jr GS. Evolution of the primary immune response to Histoplasma capsulatum in murine lung. Infect Immun. 1998;66(4):1473–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Medeiros AI, Sa-Nunes A, Soares EG, Peres CM, Silva CL, Faccioli LH. Blockade of endogenous leukotrienes exacerbates pulmonary histoplasmosis. Infect Immun. 2004;72(3):1637–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294(5548):1871–5. doi:10.1126/science.294.5548.1871.

    Article  CAS  PubMed  Google Scholar 

  30. Harris SG, Padilla J, Koumas L, Ray D, Phipps RP. Prostaglandins as modulators of immunity. Trends Immunol. 2002;23(3):144–50.

    Article  CAS  PubMed  Google Scholar 

  31. Betz M, Fox BS. Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J Immunol. 1991;146(1):108–13.

    CAS  PubMed  Google Scholar 

  32. Aronoff DM, Canetti C, Peters-Golden M. Prostaglandin E2 inhibits alveolar macrophage phagocytosis through an E-prostanoid 2 receptor-mediated increase in intracellular cyclic AMP. J Immunol. 2004;173(1):559–65.

    Article  CAS  PubMed  Google Scholar 

  33. Aronoff DM, Canetti C, Serezani CH, Luo M, Peters-Golden M. Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1. J Immunol. 2005;174(2):595–9.

    Article  CAS  PubMed  Google Scholar 

  34. Secatto A, Rodrigues LC, Serezani CH, Ramos SG, Dias-Baruffi M, Faccioli LH, et al. 5-Lipoxygenase deficiency impairs innate and adaptive immune responses during fungal infection. PLoS One. 2012;7(3), e31701. doi:10.1371/journal.pone.0031701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Belanger C, Elimam H, Lefebvre J, Borgeat P, Marleau S. Involvement of endogenous leukotriene B4 and platelet-activating factor in polymorphonuclear leucocyte recruitment to dermal inflammatory sites in rats. Immunology. 2008;124(3):295–303. doi:10.1111/j.1365-2567.2007.02767.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kurita N, Brummer E, Yoshida S, Nishimura K, Miyaji M. Antifungal activity of murine polymorphonuclear neutrophils against Histoplasma capsulatum. J Med Vet Mycol. 1991;29(3):133–43.

    Article  CAS  PubMed  Google Scholar 

  37. Brummer E, Kurita N, Yosihida S, Nishimura K, Miyaji M. Fungistatic activity of human neutrophils against Histoplasma capsulatum: correlation with phagocytosis. J Infect Dis. 1991;164(1):158–62.

    Article  CAS  PubMed  Google Scholar 

  38. Medeiros AI, Secatto A, Belanger C, Sorgi CA, Borgeat P, Marleau S, et al. Impairment of neutrophil migration to remote inflammatory site during lung histoplasmosis. Biomed Res Int. 2015;2015:409309. doi:10.1155/2015/409309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Sa-Nunes A, Medeiros AI, Sorgi CA, Soares EG, Maffei CM, Silva CL, et al. Gr-1+ cells play an essential role in an experimental model of disseminated histoplasmosis. Microbes Infect. 2007;9(12–13):1393–401. doi:10.1016/j.micinf.2006.10.007.

    Article  CAS  PubMed  Google Scholar 

  40. Zhou P, Miller G, Seder RA. Factors involved in regulating primary and secondary immunity to infection with Histoplasma capsulatum: TNF-alpha plays a critical role in maintaining secondary immunity in the absence of IFN-gamma. J Immunol. 1998;160(3):1359–68.

    CAS  PubMed  Google Scholar 

  41. Fecher RA, Horwath MC, Friedrich D, Rupp J, Deepe Jr GS. Inverse correlation between IL-10 and HIF-1alpha in macrophages infected with Histoplasma capsulatum. J Immunol. 2016;197(2):565–79. doi:10.4049/jimmunol.1600342.

    Article  CAS  PubMed  Google Scholar 

  42. Smith WL, Meade EA, DeWitt DL. Pharmacology of prostaglandin endoperoxide synthase isozymes-1 and -2. Ann N Y Acad Sci. 1994;714:136–42.

    Article  CAS  PubMed  Google Scholar 

  43. MacKenzie KF, Clark K, Naqvi S, McGuire VA, Noehren G, Kristariyanto Y, et al. PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol. 2013;190(2):565–77. doi:10.4049/jimmunol.1202462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shibata Y, Henriksen RA, Honda I, Nakamura RM, Myrvik QN. Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG. J Leukoc Biol. 2005;78(6):1281–90. doi:10.1189/jlb.0605321.

    Article  CAS  PubMed  Google Scholar 

  45. Pereira PA, Trindade BC, Secatto A, Nicolete R, Peres-Buzalaf C, Ramos SG, et al. Celecoxib improves host defense through prostaglandin inhibition during Histoplasma capsulatum infection. Mediat Inflamm. 2013;2013:950981. doi:10.1155/2013/950981.

    Article  CAS  Google Scholar 

  46. Kurihara T, Warr G, Loy J, Bravo R. Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J Exp Med. 1997;186(10):1757–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7(3):311–7. doi:10.1038/ni1309.

    Article  CAS  PubMed  Google Scholar 

  48. Djennane S, Chauvin JE, Meyer C. Glasshouse behaviour of eight transgenic potato clones with a modified nitrate reductase expression under two fertilization regimes. J Exp Bot. 2002;53(371):1037–45.

    Article  CAS  PubMed  Google Scholar 

  49. Traynor TR, Kuziel WA, Toews GB, Huffnagle GB. CCR2 expression determines T1 versus T2 polarization during pulmonary Cryptococcus neoformans infection. J Immunol. 2000;164(4):2021–7.

    Article  CAS  PubMed  Google Scholar 

  50. Warmington KS, Boring L, Ruth JH, Sonstein J, Hogaboam CM, Curtis JL, et al. Effect of C-C chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses. Am J Pathol. 1999;154(5):1407–16. doi:10.1016/S0002-9440(10)65394-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jia T, Serbina NV, Brandl K, Zhong MX, Leiner IM, Charo IF, et al. Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection. J Immunol. 2008;180(10):6846–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Peters W, Dupuis M, Charo IF. A mechanism for the impaired IFN-gamma production in C-C chemokine receptor 2 (CCR2) knockout mice: role of CCR2 in linking the innate and adaptive immune responses. J Immunol. 2000;165(12):7072–7.

    Article  CAS  PubMed  Google Scholar 

  53. Winters MS, Chan Q, Caruso JA, Deepe Jr GS. Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses. J Infect Dis. 2010;202(7):1136–45. doi:10.1086/656191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J Allergy Clin Immunol. 2013;132(1):205–13. doi:10.1016/j.jaci.2013.03.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Verma AH, Bueter CL, Rothenberg ME, Deepe GS. Eosinophils subvert host resistance to an intracellular pathogen by instigating non-protective IL-4 in CCR2-/- mice. Mucosal Immunol. 2016. doi:10.1038/mi.2016.26.

    PubMed  PubMed Central  Google Scholar 

  56. Sattler S, Smits HH, Xu D, Huang FP. The evolutionary role of the IL-33/ST2 system in host immune defence. Arch Immunol Ther Exp (Warsz). 2013;61(2):107–17. doi:10.1007/s00005-012-0208-8.

    Article  CAS  Google Scholar 

  57. Verma A, Kroetz DN, Tweedle JL, Deepe Jr GS. Type II cytokines impair host defense against an intracellular fungal pathogen by amplifying macrophage generation of IL-33. Mucosal Immunol. 2015;8(2):380–9. doi:10.1038/mi.2014.75.

    Article  CAS  PubMed  Google Scholar 

  58. Deepe Jr GS, Gibbons R, Woodward E. Neutralization of endogenous granulocyte-macrophage colony-stimulating factor subverts the protective immune response to Histoplasma capsulatum. J Immunol. 1999;163(9):4985–93.

    CAS  PubMed  Google Scholar 

  59. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, Caruso JA, Deepe Jr GS. Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity. 2013;39(4):697–710. doi:10.1016/j.immuni.2013.09.006.

    Article  CAS  PubMed  Google Scholar 

  60. Ramsey SA, Klemm SL, Zak DE, Kennedy KA, Thorsson V, Li B, et al. Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics. PLoS Comput Biol. 2008;4(3), e1000021. doi:10.1371/journal.pcbi.1000021.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Lopez Campos GN, Velarde Felix JS, Sandoval Ramirez L, Cazares Salazar S, Corona Nakamura AL, Amaya Tapia G, et al. Polymorphism in cathelicidin gene (CAMP) that alters hypoxia-inducible factor (HIF-1alpha::ARNT) binding is not associated with tuberculosis. Int J Immunogenet. 2014;41(1):54–62. doi:10.1111/iji.12080.

    Article  CAS  PubMed  Google Scholar 

  62. Nizet V, Ohtake T, Lauth X, Trowbridge J, Rudisill J, Dorschner RA, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;414(6862):454–7. doi:10.1038/35106587.

    Article  CAS  PubMed  Google Scholar 

  63. Zhu G, Tang Y, Geng N, Zheng M, Jiang J, Li L, et al. HIF-alpha/MIF and NF-kappaB/IL-6 axes contribute to the recruitment of CD11b+Gr-1+ myeloid cells in hypoxic microenvironment of HNSCC. Neoplasia. 2014;16(2):168–79. doi:10.1593/neo.132034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117(23):e207–17. doi:10.1182/blood-2010-10-314427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Allendoerfer R, Deepe Jr GS. Intrapulmonary response to Histoplasma capsulatum in gamma interferon knockout mice. Infect Immun. 1997;65(7):2564–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Allendoerfer R, Deepe Jr GS. Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J Immunol. 1998;160(12):6072–82.

    CAS  PubMed  Google Scholar 

  67. Deepe Jr GS, Gibbons RS. Interleukins 17 and 23 influence the host response to Histoplasma capsulatum. J Infect Dis. 2009;200(1):142–51. doi:10.1086/599333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bretz C, Gersuk G, Knoblaugh S, Chaudhary N, Randolph-Habecker J, Hackman RC, et al. MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus. Infect Immun. 2008;76(3):952–8. doi:10.1128/IAI.00927-07.

    Article  CAS  PubMed  Google Scholar 

  69. Bellocchio S, Montagnoli C, Bozza S, Gaziano R, Rossi G, Mambula SS, et al. The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol. 2004;172(5):3059–69.

    Article  CAS  PubMed  Google Scholar 

  70. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 1998;9(1):143–50.

    Article  CAS  PubMed  Google Scholar 

  71. Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell. 1998;2(2):253–8.

    Article  CAS  PubMed  Google Scholar 

  72. Coady A, Sil A. MyD88-dependent signaling drives host survival and early cytokine production during Histoplasma capsulatum infection. Infect Immun. 2015;83(4):1265–75. doi:10.1128/IAI.02619-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sundblad V, Croci DO, Rabinovich GA. Regulated expression of galectin-3, a multifunctional glycan-binding protein, in haematopoietic and non-haematopoietic tissues. Histol Histopathol. 2011;26(2):247–65.

    CAS  PubMed  Google Scholar 

  74. Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG. Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J Immunol. 2002;168(4):1813–22.

    Article  CAS  PubMed  Google Scholar 

  75. Bernardes ES, Silva NM, Ruas LP, Mineo JR, Loyola AM, Hsu DK, et al. Toxoplasma gondii infection reveals a novel regulatory role for galectin-3 in the interface of innate and adaptive immunity. Am J Pathol. 2006;168(6):1910–20. doi:10.2353/ajpath.2006.050636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ge XN, Bahaie NS, Kang BN, Hosseinkhani MR, Ha SG, Frenzel EM, et al. Allergen-induced airway remodeling is impaired in galectin-3-deficient mice. J Immunol. 2010;185(2):1205–14. doi:10.4049/jimmunol.1000039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ferraz LC, Bernardes ES, Oliveira AF, Ruas LP, Fermino ML, Soares SG, et al. Lack of galectin-3 alters the balance of innate immune cytokines and confers resistance to Rhodococcus equi infection. Eur J Immunol. 2008;38(10):2762–75. doi:10.1002/eji.200737986.

    Article  CAS  PubMed  Google Scholar 

  78. Jiang HR, Al Rasebi Z, Mensah-Brown E, Shahin A, Xu D, Goodyear CS, et al. Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J Immunol. 2009;182(2):1167–73.

    Article  CAS  PubMed  Google Scholar 

  79. Ruas LP, Bernardes ES, Fermino ML, de Oliveira LL, Hsu DK, Liu FT, et al. Lack of galectin-3 drives response to Paracoccidioides brasiliensis toward a Th2-biased immunity. PLoS One. 2009;4(2), e4519. doi:10.1371/journal.pone.0004519.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Wu SY, Yu JS, Liu FT, Miaw SC, Wu-Hsieh BA. Galectin-3 negatively regulates dendritic cell production of IL-23/IL-17-axis cytokines in infection by Histoplasma capsulatum. J Immunol. 2013;190(7):3427–37. doi:10.4049/jimmunol.1202122.

    Article  CAS  PubMed  Google Scholar 

  81. Chamilos G, Ganguly D, Lande R, Gregorio J, Meller S, Goldman WE, et al. Generation of IL-23 producing dendritic cells (DCs) by airborne fungi regulates fungal pathogenicity via the induction of T(H)-17 responses. PLoS One. 2010;5(9), e12955. doi:10.1371/journal.pone.0012955.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Wang H, LeBert V, Hung CY, Galles K, Saijo S, Lin X, et al. C-type lectin receptors differentially induce th17 cells and vaccine immunity to the endemic mycosis of North America. J Immunol. 2014;192(3):1107–19. doi:10.4049/jimmunol.1302314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nanjappa SG, Heninger E, Wuthrich M, Gasper DJ, Klein BS. Tc17 cells mediate vaccine immunity against lethal fungal pneumonia in immune deficient hosts lacking CD4+ T cells. PLoS Pathog. 2012;8(7), e1002771. doi:10.1371/journal.ppat.1002771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xiong Y, Lingrel JB, Wuthrich M, Klein BS, Vasudevan NT, Jain MK et al. Transcription factor KLF2 in dendritic cells downregulates Th2 programming via the HIF-1alpha/Jagged2/Notch Axis. MBio. 2016;7(3). doi:10.1128/mBio.00436-16.

  85. Pina A, de Araujo EF, Felonato M, Loures FV, Feriotti C, Bernardino S, et al. Myeloid dendritic cells (DCs) of mice susceptible to paracoccidioidomycosis suppress T cell responses whereas myeloid and plasmacytoid DCs from resistant mice induce effector and regulatory T cells. Infect Immun. 2013;81(4):1064–77. doi:10.1128/IAI.00736-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Deepe Jr GS, Gibbons RS. TNF-alpha antagonism generates a population of antigen-specific CD4+CD25+ T cells that inhibit protective immunity in murine histoplasmosis. J Immunol. 2008;180(2):1088–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ueno K, Urai M, Ohkouchi K, Miyazaki Y, Kinjo Y. Dendritic cell-based vaccine against fungal infection. Methods Mol Biol. 2016;1403:537–49. doi:10.1007/978-1-4939-3387-7_30.

    Article  PubMed  Google Scholar 

  88. Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624–34. doi:10.1016/j.jaci.2013.01.052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Odio CD, Milligan KL, McGowan K, Rudman Spergel AK, Bishop R, Boris L, et al. Endemic mycoses in patients with STAT3-mutated hyper-IgE (Job) syndrome. J Allergy Clin Immunol. 2015;136(5), 1411–3.e1-2. doi:10.1016/j.jaci.2015.07.003.

    Article  PubMed  CAS  Google Scholar 

  90. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20(1):115–32. doi:10.1128/CMR.00027-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Holbrook ED, Kemski MM, Richer SM, Wheat LJ, Rappleye CA. Glycosylation and immunoreactivity of the Histoplasma capsulatum Cfp4 yeast-phase exoantigen. Infect Immun. 2014;82(10):4414–25. doi:10.1128/IAI.01893-14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Toyotome T, Watanabe A, Ochiai E, Kamei K. N-acetylated alpha-linked acidic dipeptidase is identified as an antigen of Histoplasma capsulatum. Biochem Biophys Res Commun. 2015;458(3):483–7. doi:10.1016/j.bbrc.2015.01.129.

    Article  CAS  PubMed  Google Scholar 

  93. Muraosa Y, Toyotome T, Yahiro M, Watanabe A, Shikanai-Yasuda MA, Kamei K. Detection of Histoplasma capsulatum from clinical specimens by cycling probe-based real-time PCR and nested real-time PCR. Med Mycol. 2016;54(4):433–8. doi:10.1093/mmy/myv106.

    Article  PubMed  Google Scholar 

  94. Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med. 1986;314(2):83–8. doi:10.1056/NEJM198601093140205.

    Article  CAS  PubMed  Google Scholar 

  95. Connolly PA, Durkin MM, Lemonte AM, Hackett EJ, Wheat LJ. Detection of Histoplasma antigen by a quantitative enzyme immunoassay. Clin Vaccine Immunol. 2007;14(12):1587–91. doi:10.1128/CVI.00071-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cunningham L, Cook A, Hanzlicek A, Harkin K, Wheat J, Goad C, et al. Sensitivity and specificity of Histoplasma antigen detection by enzyme immunoassay. J Am Anim Hosp Assoc. 2015;51(5):306–10. doi:10.5326/JAAHA-MS-6202.

    Article  PubMed  Google Scholar 

  97. Cordeiro RA, Teixeira CE, Brilhante RS, Castelo-Branco DS, Paiva MA, Giffoni Leite JJ, et al. Minimum inhibitory concentrations of amphotericin B, azoles and caspofungin against Candida species are reduced by farnesol. Med Mycol. 2013;51(1):53–9. doi:10.3109/13693786.2012.692489.

    Article  CAS  PubMed  Google Scholar 

  98. Brilhante RS, de Lima RA, Marques FJ, Silva NF, Caetano EP, Castelo-Branco Dde S, et al. Histoplasma capsulatum in planktonic and biofilm forms: in vitro susceptibility to amphotericin B, itraconazole and farnesol. J Med Microbiol. 2015;64(Pt 4):394–9. doi:10.1099/jmm.0.000030.

    Article  CAS  PubMed  Google Scholar 

  99. Sardi Jde C, Pitangui Nde S, Rodriguez-Arellanes G, Taylor ML, Fusco-Almeida AM, Mendes-Giannini MJ. Highlights in pathogenic fungal biofilms. Rev Iberoam Micol. 2014;31(1):22–9. doi:10.1016/j.riam.2013.09.014.

    Article  PubMed  Google Scholar 

  100. Seyedmousavi S, Verweij PE, Mouton JW. Isavuconazole, a broad-spectrum triazole for the treatment of systemic fungal diseases. Expert Rev Anti-Infect Ther. 2015;13(1):9–27. doi:10.1586/14787210.2015.990382.

    Article  CAS  PubMed  Google Scholar 

  101. Edwards JA, Kemski MM, Rappleye CA. Identification of an aminothiazole with antifungal activity against intracellular Histoplasma capsulatum. Antimicrob Agents Chemother. 2013;57(9):4349–59. doi:10.1128/AAC.00459-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Khalil A, Edwards JA, Rappleye CA, Tjarks W. Design, synthesis, and biological evaluation of aminothiazole derivatives against the fungal pathogens Histoplasma capsulatum and Cryptococcus neoformans. Bioorg Med Chem. 2015;23(3):532–47. doi:10.1016/j.bmc.2014.12.006.

    Article  CAS  PubMed  Google Scholar 

  103. Cordeiro Rde A, Marques FJ, Brilhante RS, Rocha de Castro ESK, Mourao CI, Caetano EP, et al. Synergistic effect of antituberculosis drugs and azoles in vitro against Histoplasma capsulatum var. capsulatum. Antimicrob Agents Chemother. 2011;55(9):4482–4. doi:10.1128/AAC.01471-10.

    Article  PubMed  CAS  Google Scholar 

  104. de Aguiar Cordeiro R, de Farias Marques FJ, da Silva MR, Donato Maia Malaquias A, Silva de Melo CV, Mafezoli J, et al. Synthesis and antifungal activity in vitro of isoniazid derivatives against Histoplasma capsulatum var. capsulatum. Antimicrob Agents Chemother. 2014;58(5):2504–11. doi:10.1128/AAC.01654-13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Brilhante RS, Caetano EP, Lima RA, Castelo Branco DS, Serpa R, Oliveira JS, et al. In vitro antifungal activity of miltefosine and levamisole: their impact on ergosterol biosynthesis and cell permeability of dimorphic fungi. J Appl Microbiol. 2015;119(4):962–9. doi:10.1111/jam.12891.

    Article  CAS  PubMed  Google Scholar 

  106. Thomaz L, Nosanchuk JD, Rossi DC, Travassos LR, Taborda CP. Monoclonal antibodies to heat shock protein 60 induce a protective immune response against experimental Paracoccidioides lutzii. Microbes Infect. 2014;16(9):788–95. doi:10.1016/j.micinf.2014.08.004.

    Article  CAS  PubMed  Google Scholar 

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    Authors and Affiliations

    1. Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267-0560, USA

      Jamie L Tweedle, Ye Xiong & George S Deepe Jr

    2. Program of Pathobiology and Molecular Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, 45267, USA

      Jamie L Tweedle

    3. Veterans Affairs Hospital, Cincinnati, OH, 45220, USA

      George S Deepe Jr

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    1. Jamie L Tweedle
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    Jamie L. Tweedle, Ye Xiong, and George S. Deepe Jr declare that they have no conflict of interest.

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    This article is part of the Topical Collection on Fungal Genomics and Pathogenesis

    Jamie L Tweedle and Ye Xiong contributed equally to this work.

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    Tweedle, J.L., Xiong, Y. & Deepe, G.S. Pathogen–Host Interaction of Histoplasma capsulatum: an Update. Curr Fungal Infect Rep 10, 153–162 (2016). https://doi.org/10.1007/s12281-016-0267-0

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