Current Fungal Infection Reports

, Volume 9, Issue 4, pp 253–258 | Cite as

Pathogenesis of Coccidioidomycosis

  • Neil M. Ampel
  • Susan E. HooverEmail author
Fungal Genomics and Pathogenesis (S Shoham, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Fungal Genomics and Pathogenesis


Coccidioidomycosis is a systemic fungal infection endemic to the American Southwest, caused by Coccidioides immitis and Coccidioides posadasii. The infection has a wide variety of clinical manifestations in humans, from asymptomatic infection to severe disease. Infection occurs through inhalation of fungal spores, leading to primary pulmonary infection and occasionally to hematogenous dissemination to other sites. Both fungal and host factors contribute to pathogenesis of this infection. Cellular and innate immune responses are involved in the protective response in both humans and mice. This review summarizes recent research on microbial and host factors involved in the pathogenesis of coccidioidomycosis.


Coccidioides Coccidioidomycosis Innate and adaptive immunity Virulence factors Systemic fungal infection Fungal infection Coccidioidomycosis pathogenesis Fungal pathogenesis 


Compliance with Ethics Guidelines

Conflict of Interest

Neil M. Ampel and Susan E. Hoover declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Smith CE, Beard RR, et al. Varieties of coccidioidal infection in relation to the epidemiology and control of the diseases. Am J Public Health Nation’s Health. 1946;36(12):1394–402.CrossRefGoogle Scholar
  2. 2.
    Chang DC, Anderson S, Wannemuehler K, Engelthaler DM, Erhart L, Sunenshine RH, et al. Testing for coccidioidomycosis among patients with community-acquired pneumonia. Emerg Infect Dis. 2008;14(7):1053–9. doi: 10.3201/eid1407.070832.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Valdivia L, Nix D, Wright M, Lindberg E, Fagan T, Lieberman D, et al. Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerg Infect Dis. 2006;12(6):958–62.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Galgiani JN. Coccdioidomycosis (Coccidioides species). In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Philadelphia: Churchill Livingstone; 2015. p. 2974–84.e3.Google Scholar
  5. 5.
    Ampel NM. The complex immunology of human coccidioidomycosis. Ann N Y Acad Sci. 2007;1111:245–58. doi: 10.1196/annals.1406.032.CrossRefPubMedGoogle Scholar
  6. 6.
    Li L, Dial SM, Schmelz M, Rennels MA, Ampel NM. Cellular immune suppressor activity resides in lymphocyte cell clusters adjacent to granulomata in human coccidioidomycosis. Infect Immun. 2005;73(7):3923–8. doi: 10.1128/iai.73.7.3923-3928.2005.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Hung CY, Xue J, Cole GT. Virulence mechanisms of coccidioides. Ann N Y Acad Sci. 2007;1111:225–35. doi: 10.1196/annals.1406.020.CrossRefPubMedGoogle Scholar
  8. 8.
    Hung CY, Seshan KR, Yu JJ, Schaller R, Xue J, Basrur V, et al. A metalloproteinase of Coccidioides posadasii contributes to evasion of host detection. Infect Immun. 2005;73(10):6689–703. doi: 10.1128/iai.73.10.6689-6703.2005.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Li J, Zhang KQ. Independent expansion of zincin metalloproteinases in Onygenales fungi may be associated with their pathogenicity. PLoS One. 2014;9(2), e90225. doi: 10.1371/journal.pone.0090225.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Gonzalez A, Hung CY, Cole GT. Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages. Microb Pathog. 2011;50(2):100–8. doi: 10.1016/j.micpath.2010.11.006.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Gonzalez A, Hung CY, Cole GT. Nitric oxide synthase activity has limited influence on the control of Coccidioides infection in mice. Microb Pathog. 2011;51(3):161–8. doi: 10.1016/j.micpath.2011.03.013.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.•
    Wise HZ, Hung CY, Whiston E, Taylor JW, Cole GT. Extracellular ammonia at sites of pulmonary infection with Coccidioides posadasii contributes to severity of the respiratory disease. Microb Pathog. 2013;59–60:19–28. doi: 10.1016/j.micpath.2013.04.003. This paper provides evidence for the role of ammonia production in Coccidioides virulence.
  13. 13.
    Mirbod-Donovan F, Schaller R, Hung CY, Xue J, Reichard U, Cole GT. Urease produced by Coccidioides posadasii contributes to the virulence of this respiratory pathogen. Infect Immun. 2006;74(1):504–15. doi: 10.1128/iai.74.1.504-515.2006.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Borchers AT, Gershwin ME. The immune response in coccidioidomycosis. Autoimmun Rev. 2010. doi: S1568-9972(10)00178-3Google Scholar
  15. 15.
    Cox RA, Magee DM. Coccidioidomycosis: host response and vaccine development. Clin Microbiol Rev. 2004;17(4):804–39.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Wüthrich M, Hung CY, Gern BH, Pick-Jacobs JC, Galles KJ, Filutowicz HI, et al. A TCR transgenic mouse reactive with multiple systemic dimorphic fungi. J Immunol. 2011;187(3):1421–31. doi: 10.4049/jimmunol.1100921.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Hung CY, Hurtgen BJ, Bellecourt M, Sanderson SD, Morgan EL, Cole GT. An agonist of human complement fragment C5a enhances vaccine immunity against Coccidioides infection. Vaccine. 2012;30(31):4681–90. doi: 10.1016/j.vaccine.2012.04.084.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Hung CY, Castro-Lopez N, Cole GT. Vaccinated C57BL/6 mice develop protective and memory T cell responses to Coccidioides posadasii infection in the absence of interleukin-10. Infect Immun. 2014;82(2):903–13. doi: 10.1128/IAI.01148-13.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Hurtgen BJ, Hung CY, Ostroff GR, Levitz SM, Cole GT. Construction and evaluation of a novel recombinant T cell epitope-based vaccine against coccidioidomycosis. Infect Immun. 2012;80(11):3960–74. doi: 10.1128/IAI.00566-12.PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Woelk CH, Zhang JX, Walls L, Viriyakosol S, Singhania A, Kirkland TN, et al. Factors regulated by interferon gamma and hypoxia-inducible factor 1A contribute to responses that protect mice from Coccidioides immitis infection. BMC Microbiol. 2012;12:218. doi: 10.1186/1471-2180-12-218.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Viriyakosol S, Jimenez Mdel P, Gurney MA, Ashbaugh ME, Fierer J. Dectin-1 is required for resistance to coccidioidomycosis in mice. mBio. 2013;4(1). doi: 10.1128/mBio.00597-12.
  22. 22.
    Viriyakosol S, Jimenez Mdel P, Saijo S, Fierer J. Neither dectin-2 nor the mannose receptor is required for resistance to Coccidioides immitis in mice. Infect Immun. 2014;82(3):1147–56. doi: 10.1128/IAI.01355-13.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Dionne SO, Podany AB, Ruiz YW, Ampel NM, Galgiani JN, Lake DF. Spherules derived from Coccidioides posadasii promote human dendritic cell maturation and activation. Infect Immun. 2006;74(4):2415–22.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    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.PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.•
    Wüthrich M, Gern B, Hung CY, Ersland K, Rocco N, Pick-Jacobs J, et al. Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice. J Clin Invest. 2011;121(2):554–68. doi: 10.1172/JCI43984. This paper describes the importance of Th17 cells in the induction of vaccine immunity not just in experimental murine coccidioidomycosis but also in histoplasmosis and blastomycosis. PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Drummond RA, Saijo S, Iwakura Y, Brown GD. The role of Syk/CARD9 coupled C-type lectins in antifungal immunity. Eur J Immunol. 2011;41(2):276–81. doi: 10.1002/eji.201041252.PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Hung CY, Jimenez-Alzate Mdel P, Gonzalez A, Wuthrich M, Klein BS, Cole GT. Interleukin-1 receptor but not Toll-like receptor 2 is essential for MyD88-dependent Th17 immunity to Coccidioides infection. Infect Immun. 2014;82(5):2106–14. doi: 10.1128/IAI.01579-13.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Nesbit L, Johnson SM, Pappagianis D, Ampel NM. Polyfunctional T lymphocytes are in the peripheral blood of donors naturally immune to coccidioidomycosis and are not induced by dendritic cells. Infect Immun. 2010;78(1):309–15.Google Scholar
  29. 29.
    Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med. 2007;13(7):843–50. doi: 10.1038/nm1592.CrossRefPubMedGoogle Scholar
  30. 30.
    Nesbit LA, Knox KS, Nguyen CT, Roesch J, Wheat LJ, Johnson SM, et al. Immunological characterization of bronchoalveolar lavage fluid in patients with acute pulmonary coccidioidomycosis. J Infect Dis. 2013;208(5):857–63. doi: 10.1093/infdis/jit246.CrossRefPubMedGoogle Scholar
  31. 31.
    Ampel NM, Nesbit LA, Nguyen CT, Chavez S, Knox KS, Johnson SM, et al. Cytokine profiles from antigen-stimulated whole blood samples among patients with pulmonary and non-meningeal disseminated coccidioidomycosis. Clin Vaccine Immunol. 2015. doi: 10.1128/CVI.00280-15.PubMedGoogle Scholar
  32. 32.•
    Lee CY, Thompson III GR, Hastey CJ, Hodge GC, Lunetta JM, Pappagianis D, et al. Coccidioides endospores and spherules draw strong chemotactic, adhesive, and phagocytic responses by individual human neutrophils. PLoS One. 2015;10(6), e0129522. doi: 10.1371/journal.pone.0129522. This paper examines the single-cell response of neutrophils to coccidioidal endospores and concludes that neutrophils demonstrate vigorous chemotaxis but frustrated phagocytosis to these structures. PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Vucicevic D, Carey EJ, Blair JE. Coccidioidomycosis in liver transplant recipients in an endemic area. Am J Transplant : Off J Am Soc Transplant Am Soc Transplant Surg. 2011;11(1):111–9. doi: 10.1111/j.1600-6143.2010.03328.x.CrossRefGoogle Scholar
  34. 34.
    Vikram HR, Dosanjh A, Blair JE. Coccidioidomycosis and lung transplantation. Transplantation. 2011;92(7):717–21. doi: 10.1097/TP.0b013e31822e6e9a.CrossRefPubMedGoogle Scholar
  35. 35.
    Braddy CM, Heilman RL, Blair JE. Coccidioidomycosis after renal transplantation in an endemic area. Am J Transplant : Off J Am Soc Transplant Am Soc Transplant Surg. 2006;6(2):340–5. doi: 10.1111/j.1600-6143.2005.01169.x.CrossRefGoogle Scholar
  36. 36.••
    Kahn A, Carey EJ, Blair JE. Universal fungal prophylaxis and risk of coccidioidomycosis in liver transplant recipients living in an endemic area. Liver Transplant : Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2015;21(3):353–61. doi: 10.1002/lt.24055. This paper updates our current state of knowledge about the risk of coccidioidomycosis in solid-organ transplant recipients. CrossRefGoogle Scholar
  37. 37.•
    Mendoza N, Noel P, Blair JE. Diagnosis, treatment, and outcomes of coccidioidomycosis in allogeneic stem cell transplantation. Transplant Infect Dis : Off J Transplant Soc. 2015. doi: 10.1111/tid.12372. This paper reports the largest series of coccidioidomycosis infections in stem cell transplant recipients to date. Google Scholar
  38. 38.
    Bergstrom L, Yocum DE, Ampel NM, Villanueva I, Lisse J, Gluck O, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum. 2004;50(6):1959–66. doi: 10.1002/art.20454.CrossRefPubMedGoogle Scholar
  39. 39.
    Mertz LE, Blair JE. Coccidioidomycosis in rheumatology patients: incidence and potential risk factors. Ann N Y Acad Sci. 2007;1111:343–57. doi: 10.1196/annals.1406.027.CrossRefPubMedGoogle Scholar
  40. 40.•
    Taroumian S, Knowles SL, Lisse JR, Yanes J, Ampel NM, Vaz A, et al. Management of coccidioidomycosis in patients receiving biologic response modifiers or disease-modifying antirheumatic drugs. Arthritis Care Res. 2012;64(12):1903–9. doi: 10.1002/acr.21784. This paper systematically describes management and outcomes for patients who developed coccidioidomycosis while taking biologic response modifiers. CrossRefGoogle Scholar
  41. 41.
    Nguyen C, Barker BM, Hoover S, Nix DE, Ampel NM, Frelinger JA, et al. Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis. Clin Microbiol Rev. 2013;26(3):505–25. doi: 10.1128/cmr.00005-13.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Vinh DC, Masannat F, Dzioba RB, Galgiani JN, Holland SM. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-gamma receptor 1 deficiency. Clin Infect Dis. 2009;49(6):e62–5. doi: 10.1086/605532.PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Vinh DC, Schwartz B, Hsu AP, Miranda DJ, Valdez PA, Fink D, et al. Interleukin-12 receptor beta1 deficiency predisposing to disseminated Coccidioidomycosis. Clin Infect Dis. 2011;52(4):e99–102. doi: 10.1093/cid/ciq215.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.•
    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. This paper describes two cases of severe coccidioidomycosis in patients with specific defects in the IFN-γ response pathway. PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    Cole GT, Hurtgen BJ, Hung CY. Progress toward a human vaccine against coccidioidomycosis. Curr Fungal Infect Rep. 2012;6(4):235–44. doi: 10.1007/s12281-012-0105-y.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.1-111 SAVAHCSTucsonUSA
  2. 2.Sanford HealthSioux FallsUSA

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