Skip to main content

Advertisement

SpringerLink
Log in

Immunization Strategies for the Control of Histoplasmosis

  • Tropical Mycoses (L Martinez, Section Editor)
  • Published:
Current Tropical Medicine Reports Aims and scope Submit manuscript

Abstract

Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum. Histoplasmosis is typically self-limited and presents asymptomatically in most people. Nevertheless, histoplasmosis can cause severe pulmonary disease and death. Histoplasmosis is increasingly found worldwide; however, it is best documented in the endemic region of the Mississippi river valley system in the Eastern part of the United States (US). Epidemiological studies from the US detailing the morbidity, mortality, and cost associated with histoplasmosis underscore the need to develop a vaccine.

Purpose of Review

This review will detail some of the major developments in potential vaccines against histoplasmosis, with particular emphasis on those that could be used to immunize immunocompromised hosts. Additionally, this review will highlight some non-traditional vaccine-like ideas for the prevention of diverse mycoses.

Recent Findings

Historically, immunization strategies against histoplasmosis have largely focused on identifying immunogenic proteins that confer protection in animal models. More recently, novel active, therapeutic, and immunomodulatory strategies have been explored as potential alternatives for those with various immune deficiencies.

Summary

The studies summarized in this review demonstrate that more research is needed to clarify the immunobiology, clinical role, and efficacy of each candidate vaccine in the ever-expanding potential armamentarium against histoplasmosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Antinori S. Histoplasma capsulatum: more widespread than previously thought. Am J Trop Med Hyg. 2014;90:982–3.

    Article  Google Scholar 

  2. Deepe GS. Outbreaks of histoplasmosis: the spores set sail. PLoS Pathog. 2018;14:1–5.

    Article  Google Scholar 

  3. Bahr NC, Antinori S, Wheat LJ, Sarosi GA. Histoplasmosis infections worldwide: thinking outside of the Ohio River valley. Curr Trop Med Rep. 2015;2:70–80.

    Article  Google Scholar 

  4. Chu JH, Feudtner C, Heydon K, Walsh TJ, Zaoutis TE. Hospitalizations for endemic mycoses: a population-based national study. Clin Infect Dis. 2006;42:822–5.

    Article  Google Scholar 

  5. Manos NE, Ferebee SH, Kerschbaum WF. Geographic variation in the prevalence of histoplasmin sensitivity. Dis Chest. 1956;29:649–68.

    Article  CAS  Google Scholar 

  6. Armstrong PA, Jackson BR, Haselow D, Fields V, Ireland M, Austin C, et al. Multistate epidemiology of histoplasmosis, United States, 2011–2014. 2018;24:425–31.

  7. Wheat J, Marichal P, Bossche HV, Monte AL, Connolly PA. Hypothesis on the mechanism of resistance to fluconazole in histoplasma capsulatum. Antimicrob Agents Chemother. 1997;41:410–4.

    Article  CAS  Google Scholar 

  8. Deepe GS, Gibbons RS, Smulian AG. Histoplasma capsulatum manifests preferential invasion of phagocytic subpopulations in murine lungs. J Leukoc Biol. 2008;84:669–78 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18577715.

    Article  CAS  Google Scholar 

  9. Ray SC, Rappleye CA. Flying under the radar: Histoplasma capsulatum avoidance of innate immune recognition. Semin Cell Dev Biol; 2018" please include "Available from: https://doi.org/10.1016/j.semcdb.2018.03.009

  10. Newman SL, Gootee L, Gabay JE, Selsted ME. Identification of constituents of human neutrophil azurophil granules that mediate fungistasis against Histoplasma capsulatum. Infect Immun. 2000;68:5668–72.

    Article  CAS  Google Scholar 

  11. Horwath MC, Fecher RA, Deepe G. Histoplasma capsulatum, lung infection and immunity. Future Microbiol. 2015;10:967–75.

    Article  CAS  Google Scholar 

  12. Thind SK, Taborda CP, Nosanchuk JD. Dendritic cell interactions with Histoplasma and Paracoccidioides. Virulence. 2015;6:424–32.

    Article  CAS  Google Scholar 

  13. Wood KL, Hage CA, Knox KS, Kleiman MB, Sannuti A, Day RB, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-α therapy. Am J Respir Crit Care Med. 2003;167:1279–82.

  14. Deepe, Jr. GS, Nosanchuk JD. Fungal vaccine development. Mol Princ Fungal Pathog [Internet]. American Society of Microbiology; 2006 [cited 2018 Aug 10]. p. 565–81. Available from: http://www.asmscience.org/content/book/10.1128/9781555815776.ch38

  15. Deepe GS. Modulation of infection with Histoplasma capsulatum by inhibition of tumor necrosis factor-alpha activity. Clin Infect Dis [Internet]. 2005;41 Suppl 3:S204-7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15983901.

  16. Limaye AP, Connolly PA, Sagar M, Fritsche TR, Cookson BT, Wheat LJ, et al. Transmission of Histoplasma capsulatum by organ transplantation. N Engl J Med. 2000;343:1163–6.

    Article  CAS  Google Scholar 

  17. Gomez AM, Rhodes JC, Deepe GS Jr. Antigenicity and immunogenicity of an extract from the cell wall and cell membrane of Histoplasma capsulatum yeast cells. Infect Immun. 1991;59:330–6.

    Article  CAS  Google Scholar 

  18. Gomez FJ, Gomez AM, Deepe GS Jr. Protective efficacy of a 62-kilodalton antigen, HIS-62, from the cell wall and cell membrane of Histoplasma capsulatum yeast cells. Infect Immun. 1991;59:4459–64.

    Article  CAS  Google Scholar 

  19. Gomez FJ, Gomez AM, Deepe GS. An 80-kilodalton antigen from Histoplasma capsulatum that has homology to heat shock protein 70 induces cell- mediated immune responses and protection in mice. Infect Immun. 1992;60:2565–71.

    Article  CAS  Google Scholar 

  20. Gomez FJ, Allendoerfer R, Deepe GS Jr. Vaccination with recombinant heat shock protein 60 from Histoplasma capsulatum protects mice against pulmonary histoplasmosis. Infect Immun. 1995;63:2587–95 Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7911197207696073954related:4mTJ8PE3ym0J%5Cn, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC173347/pdf/632587.pdf.

    Article  CAS  Google Scholar 

  21. Deepe G, Gibbons R, Brunner GD, Gomez FJ. A protective domain of heat-shock protein 60 from Histoplasma capsulatum. J Infect Dis. 1996;174:828–34.

    Article  CAS  Google Scholar 

  22. Clemons KV, Darbonne WC, Curnutte JT, Sobel RA, Stevens DA. Experimental histoplasmosis in mice treated with anti-murine interferon- γ antibody and in interferon-γ gene knockout mice. Microbes Infect. 2000;2:997–1001.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. Deepe GS, Gibbons RS. Cellular and molecular regulation of vaccination with heat shock protein 60 from Histoplasma capsulatum. Infect Immun [Internet]. American Society for Microbiology; 2002 [cited 2018 Jun 14];70:3759–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12065519.

  26. Scheckelhoff M, Deepe GS. The protective immune response to heat shock protein 60 of Histoplasma capsulatum is mediated by a subset of Vβ8.1/8.2+ T Cells. J Immunol [Internet]. 2002;169:5818–26. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.169.10.5818

  27. Purcell AW, McCluskey J, Rossjohn J. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov [Internet]. Nature Publishing Group; 2007;6:404–14. Available from: https://doi.org/10.1038/nrd2224.

  28. Guimarães AJ, de Cerqueira MD, Nosanchuk JD. Surface architecture of Histoplasma capsulatum. Front Microbiol. 2011;2:1–14.

    Article  Google Scholar 

  29. Reeves MW, Pine L, Bradley G. Characterization and evaluation of a soluble antigen complex prepared from the yeast phase of Histoplasma capsulatum. Infect Immun. 1974;9:1033–44.

    Article  CAS  Google Scholar 

  30. Zancopé-Oliveira RM, Bragg SL, Reiss E, Peralta JM. Immunochemical analysis of the H and M glycoproteins from Histoplasma capsulatum. Clin Diagn Lab Immunol. 1994;1:563–8 Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=368339&tool=pmcentrez&rendertype=abstract.

    Article  Google Scholar 

  31. Pine L, Malcolm GB, Gross H, Gray SB. Evaluation of purified H and M antigens of histoplasmin as reagents in the complement fixation test. Sabouraudia [Internet]. 1978;16:257–69. Available from: https://doi.org/10.1080/00362177885380361

  32. Deepe GS, Durose GG. Immunobiological activity of recombinant H antigen from Histoplasma capsulatum. Infect Immun. 1995;63:3151–7.

    Article  CAS  Google Scholar 

  33. Deepe J, Gibbons R. Protective efficacy of H antigen from Histoplasma capsulatum in a murine model of pulmonary histoplasmosis. Infect Immun. 2001;69:3128–34.

    Article  CAS  Google Scholar 

  34. •• Hsieh SH, Lin JS, Huang JH, Wu SY, Chu CL, Kung JT, et al. Immunization with apoptotic phagocytes containing Histoplasma capsulatum activates functional CD8 + T cells to protect against Histoplasmosis. Infect Immun. 2011;79:4493–502. This paper demonstrated the efficacy of cross-priming a CD8+ T cell response against histoplasmosis. This is significant in that it represents a possible active vaccination strategy for those with compromised immune systems, specifically those suffering from unmanaged HIV infection or AIDS.

    Article  CAS  Google Scholar 

  35. Tewari RP, Sharma D, Solotorovsky M, Lafemina R, Balint J. Adoptive transfer of immunity from mice immunized with ribosomes or live yeast cells of Histoplasma capsulatum. Infect Immun. 1977;15:789–95.

    Article  CAS  Google Scholar 

  36. Nosanchuk JD, Zancopé-Oliveira RM, Hamilton AJ, Guimarães AJ. Antibody therapy for histoplasmosis. Front Microbiol. 2012;3:1–7.

    Article  Google Scholar 

  37. Nosanchuk JD, Steenbergen JN, Shi L, Deepe GS, Casadevall A. Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum. J Clin Invest. 2003;112:1164–75.

    Article  CAS  Google Scholar 

  38. Shi L, Albuquerque PC, Lazar-Molnar E, Wang X, Santambrogio L, Gacser A, et al. A monoclonal antibody to Histoplasma capsulatum alters the intracellular fate of the fungus in murine macrophages. Eukaryot Cell. 2008;7:1109–17.

    Article  CAS  Google Scholar 

  39. Guimarães AJ, Frases S, Gomez FJ, Zancopé-Oliveira RM, Nosanchuk JD. Monoclonal antibodies to heat shock protein 60 alter the pathogenesis of Histoplasma capsulatum. Infect Immun [Internet]. American Society for Microbiology; 2009 [cited 2018 Jun 11];77:1357–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19179416.

  40. Guimaraes AJ, Frases S, Pontes B, de Cerqueira MD, Rodrigues ML, Viana NB, et al. Agglutination of Histoplasma capsulatum by IgG monoclonal antibodies against Hsp60 impacts macrophage effector functions. Infect Immun. 2011;79:918–27.

  41. Rodrigues ML, Alvarez M, Fonseca FL, Casadevall A. Binding of the wheat germ lectin to Cryptococcus neoformans suggests an association of chitin-like structures with yeast budding and capsular glucuronoxylomannan. Eukaryot Cell. 2008;7:602–9.

    Article  CAS  Google Scholar 

  42. •• Liedke SC, Miranda DZ, Gomes KX, Gonçalves JLS, Frases S, Nosanchuk JD, et al. Characterization of the antifungal functions of a WGA-Fc (IgG2a) fusion protein binding to cell wall chitin oligomers. Sci Rep. 2017;7:1–17. This paper is significant in that WGA-Fc (IgG2a) represents a potentially powerful passive vaccination strategy against diverse mycoses.

    Article  CAS  Google Scholar 

  43. • Bryan RA, Guimarães AJ, Hopcraft S, Jiang Z, Bonilla K, Morgenstern A, et al. Toward developing a universal treatment for fungal disease using radioimmunotherapy targeting common fungal antigens. Mycopathologia. 2012;173:463–71. This paper is significant because it demonstrates that it is possible to develop radio-immunotherapeutics against diverse mycoses. Here, the efficacy of the mAb is not necessarily dependent on cellular immunity and thus, it represents a way of passively vaccinating those with immune deficiencies in antibody-dependent cellular cytotoxicity.

    Article  CAS  Google Scholar 

  44. Qureshi A, Wray D, Rhome R, Barry W, Del Poeta M. Detection of antibody against fungal glucosylceramide in immunocompromised patients: a potential new diagnostic approach for cryptococcosis. Mycopathologia. 2012;173:419–25.

    Article  CAS  Google Scholar 

  45. Mor V, Farnoud AM, Singh A, Rella A, Tanno H, Ishii K, et al. Glucosylceramide administration as a vaccination strategy in mouse models of cryptococcosis. PLoS One. 2016:1–15.

  46. Rodrigues ML, Shi L, Barreto-Bergter E, Nimrichter L, Farias SE, Rodrigues EG, et al. Monoclonal antibody to fungal glucosylceramide protects mice against lethal Cryptococcus neoformans infection. Clin Vaccine Immunol. 2007;14:1372–6.

  47. Rhome R, Singh A, Kechichian T, Drago M, Morace G, Luberto C, et al. Surface localization of glucosylceramide during Cryptococcus neoformans infection allows targeting as a potential antifungal. PLoS One. 2011;6:e15572.

  48. Rhome R, Mcquiston T, Kechichian T, Bielawska A, Hennig M, Drago M, et al. Biosynthesis and immunogenicity of Glucosylceramide in Cryptococcus neoformans and other human pathogens. Eukaryot Cell. 2007;6:1715–26.

    Article  CAS  Google Scholar 

  49. Dermani FK, Samadi P, Rahmani G, Kohlan AK, Najafi R. PD-1/PD-L1 immune checkpoint: potential target for cancer therapy. J Cell Physiol. 2018.

  50. • Lazar-Molnar E, Gacser A, Freeman GJ, Almo SC, Nathenson SG, Nosanchuk JD. The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci. 2008;105:2658–63. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0711918105. This paper is significant in that it represents a new potential indication for PD-1R mAb.

    Article  CAS  Google Scholar 

  51. • Kumaresan PR, Manuri PR, Albert ND, Maiti S, Singh H, Mi T, et al. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci. 2014;111:10660–5. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1312789111. This paper is significant because it provided evidence that cytotoxic CD8+ T cells could be raised in vitro against diverse fungi. This engineered specific immunity is invaluable to those with various immunodeficiencies as well to those for whom standard vaccination strategies may not work.

Download references

Acknowledgments

JDN and DZM are partially supported by NIH AI124797. MTR is partially supported by an award from the IDSA Foundation and an Einstein Summer Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Medicine (Division of Infectious Diseases) and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

    Maxwell T. Roth, Daniel Zamith-Miranda & Joshua D. Nosanchuk

Authors
  1. Maxwell T. Roth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Zamith-Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joshua D. Nosanchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joshua D. Nosanchuk.

Ethics declarations

Conflict of Interest

The authors 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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Tropical Mycoses

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roth, M.T., Zamith-Miranda, D. & Nosanchuk, J.D. Immunization Strategies for the Control of Histoplasmosis. Curr Trop Med Rep 6, 35–41 (2019). https://doi.org/10.1007/s40475-019-00172-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40475-019-00172-3

Keywords

Search

Navigation