Current Tropical Medicine Reports

, Volume 6, Issue 2, pp 50–54 | Cite as

Antibody Immunity and Natural Resistance to Cryptococcosis

  • Nuria Trevijano-Contador
  • Liise-anne PirofskiEmail author
Tropical Mycosis (L Martinez, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Tropical Mycosis


Purpose of Review

To review recent data on the role that B cells and/or antibody-based immunity play in host defense against Cryptococcus neoformans (Cn).

Recent Findings

Cn, an encapsulated fungus, causes cryptococcal meningitis (CM). There are ~180,000 deaths per year worldwide attributed to CM, which is the most common cause of meningitis in adults with HIV in sub-Saharan Africa. HIV infection with advanced immunodeficiency is the most important predisposing risk factor for CM, highlighting the critical role that T cell-mediated immunity plays in disease prevention. However, numerous studies in the past decade demonstrate that antibody immunity also plays a role in resistance to CM. In mice, B cells reduce early dissemination from the lungs to the brain, and naïve mouse IgM can enhance fungal containment in the lungs. In concert with these findings, human studies show that patients with CM have lower IgM memory B cell levels and/or different serum profiles of Cn-binding and natural antibodies than controls.


There is sufficient evidence to support a possible role for B cells and certain antibodies in natural resistance to CM. This underscores the need for a deeper understanding of mechanisms by which natural and Cn-binding antibodies may reduce Cn virulence and protect against Cn dissemination and human CM.


Cryptococcus neoformans B cells Antibodies IgM Host immunity Adaptive response 



Liise-anne Pirofski was supported in part by NIH Grant AI097096.

Compliance with Ethical Standards

Conflict of Interest

Nuria Trevijano-Contador and Liise-anne Pirofski declare 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.
    Lazera MS, Salmito Cavalcanti MA, Londero AT, Trilles L, Nishikawa MM, Wanke B. Possible primary ecological niche of Cryptococcus neoformans. Med Mycol. 2000;38:379–83.CrossRefGoogle Scholar
  2. 2.
    Casadevall A, Perfect J. Cryptococcus neoformans. Washington DC: ASM; 1998.CrossRefGoogle Scholar
  3. 3.
    Rohatgi S, Pirofski LA. Host immunity to Cryptococcus neoformans. Future Microbiol. 2015;10:565–81.CrossRefGoogle Scholar
  4. 4.
    Pirofski LA, Casadevall A. Immune-mediated damage completes the parabola: Cryptococcus neoformans pathogenesis can reflect the outcome of a weak or strong immune response. mBio. 2017;8.Google Scholar
  5. 5.
    • Rajasingham R, Smith RM, Park BJ, Jarvis JN, Govender NP, Chiller TM, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017;17:873–81 Provides a circa 2014 estimate of the global incidence of HIV-associated cryptococcal disease, HIV incidence, ART access, and retention in care using published UNAIDS and cryptococcal prevalence data.CrossRefGoogle Scholar
  6. 6.
    Shaheen AA, Somayaji R, Myers R, Mody CH. Epidemiology and trends of cryptococcosis in the United States from 2000 to 2007: a population-based study. Int J STD AIDS. 2018;29:453–60.CrossRefGoogle Scholar
  7. 7.
    Enoch DA, Yang H, Aliyu SH, Micallef C. The changing epidemiology of invasive fungal infections. Methods Mol Biol. 2017;1508:17–65.CrossRefGoogle Scholar
  8. 8.
    Monga DP, Kumar R, Mohapatra LN, Malaviya AN. Experimental cryptococcosis in normal and B-cell-deficient mice. Infect Immun. 1979;26:1–3.Google Scholar
  9. 9.
    Rivera J, Casadevall A. Mouse genetic background is a major determinant of isotype-related differences for antibody-mediated protective efficacy against Cryptococcus neoformans. J Immunol. 2005;174:8017–26.CrossRefGoogle Scholar
  10. 10.
    Feldmesser M, Mednick A, Casadevall A. Antibody-mediated protection in murine Cryptococcus neoformans infection is associated with pleotrophic effects on cytokine and leukocyte responses. Infect Immun. 2002;70:1571–80.CrossRefGoogle Scholar
  11. 11.
    Datta K, Pirofski LA. Towards a vaccine for Cryptococcus neoformans: principles and caveats. FEMS Yeast Res. 2006;6:525–36.CrossRefGoogle Scholar
  12. 12.
    Casadevall A, Pirofski L. Insights into mechanisms of antibody-mediated immunity from studies with Cryptococcus neoformans. Curr Mol Med. 2005;5:421–33.CrossRefGoogle Scholar
  13. 13.
    Aguirre KM, Johnson LL. A role for B cells in resistance to Cryptococcus neoformans in mice. Infect Immun. 1997;65:525–30.Google Scholar
  14. 14.
    Moir S, Fauci AS. B cells in HIV infection and disease. Nat Rev Immunol. 2009;9:235–45.CrossRefGoogle Scholar
  15. 15.
    Lane HC, Shelhamer JH, Mostowski HS, Fauci AS. Human monoclonal anti-keyhole limpet hemocyanin antibody-secreting hybridoma produced from peripheral blood B lymphocytes of a keyhole limpet hemocyanin-immune individual. J Exp Med. 1982;155:333–8.CrossRefGoogle Scholar
  16. 16.
    •• Dufaud C, Rivera J, Rohatgi S, Pirofski LA. Naive B cells reduce fungal dissemination in Cryptococcus neoformans infected Rag1(-/-) mice. Virulence. 2018;9:173–84 This article establishes that B cells are able to reduce early Cn dissemination in mice and suggest that normal mouse IgM may be a key mediator of early antifungal immunity in the lungs.CrossRefGoogle Scholar
  17. 17.
    Rohatgi S, Pirofski LA. Molecular characterization of the early B cell response to pulmonary Cryptococcus neoformans infection. J Immunol. 2012;189:5820–30.CrossRefGoogle Scholar
  18. 18.
    • Subramaniam KS, Datta K, Quintero E, Manix C, Marks MS, Pirofski LA. The absence of serum IgM enhances the susceptibility of mice to pulmonary challenge with Cryptococcus neoformans. J Immunol. 2010;184:5755–67 This paper shows that presence of normal mouse IgM reduces Cn dissemination to the brain, promotes containment of Cn in the lungs, and enhances the phagocytic capacity of alveolar macrophages.CrossRefGoogle Scholar
  19. 19.
    • Szymczak WA, Davis MJ, Lundy SK, Dufaud C, Olszewski M, Pirofski LA. X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans Infection. mBio. 2013;4:e00265–13 This paper shows that XID mice, which lack B-1 cells and IgM, exhibit a dissemination phenotype whereby Cn disseminates from lungs to brain, and suggests that absence of IgM impairs Cn phagocytosis and allows Cn enlargment in the lungs.CrossRefGoogle Scholar
  20. 20.
    Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, et al. Mutation of unique region of Bruton’s tyrosine kinase in immunodeficient XID mice. Science. 1993;261:358–61.CrossRefGoogle Scholar
  21. 21.
    Trevijano-Contador N, Rueda C, Zaragoza O. Fungal morphogenetic changes inside the mammalian host. Semin Cell Dev Biol. 2016;57:100–9.CrossRefGoogle Scholar
  22. 22.
    • Trevijano-Contador N, de Oliveira HC, Garcia-Rodas R, Rossi SA, Llorente I, Zaballos A, et al. Cryptococcus neoformans can form titan-like cells in vitro in response to multiple signals. PLoS Pathog. 2018;14:e1007007 Provides a new method to investigate Titan cell formation in vitro. This method will make it posible to examine the effect of antibodies on Cn Titan cell formation.CrossRefGoogle Scholar
  23. 23.
    Zaragoza O, Garcia-Rodas R, Nosanchuk JD, Cuenca-Estrella M, Rodriguez-Tudela JL, Casadevall A. Fungal cell gigantism during mammalian infection. PLoS Pathog. 2010;6:e1000945.CrossRefGoogle Scholar
  24. 24.
    Okagaki LH, Wang Y, Ballou ER, O'Meara TR, Bahn YS, Alspaugh JA, et al. Cryptococcal titan cell formation is regulated by G-protein signaling in response to multiple stimuli. Eukaryot Cell. 2011;10:1306–16.CrossRefGoogle Scholar
  25. 25.
    Rapaka RR, Ricks DM, Alcorn JF, Chen K, Khader SA, Zheng M, et al. Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina. J Exp Med. 2010;207:2907–19.CrossRefGoogle Scholar
  26. 26.
    • Rachini A, Pietrella D, Lupo P, Torosantucci A, Chiani P, Bromuro C, et al. An anti-beta-glucan monoclonal antibody inhibits growth and capsule formation of Cryptococcus neoformans in vitro and exerts therapeutic, anticryptococcal activity in vivo. Infect Immun. 2007;75:5085–94.CrossRefGoogle Scholar
  27. 27.
    Fleuridor R, Lyles RH, Pirofski L. Quantitative and qualitative differences in the serum antibody profiles of human immunodeficiency virus-infected persons with and without Cryptococcus neoformans meningitis. J Infect Dis. 1999;180:1526–35.CrossRefGoogle Scholar
  28. 28.
    Subramaniam K, French N, Pirofski LA. Cryptococcus neoformans-reactive and total immunoglobulin profiles of human immunodeficiency virus-infected and uninfected Ugandans. Clin Diagn Lab Immunol. 2005;12:1168–76.Google Scholar
  29. 29.
    Deshaw M, Pirofski LA. Antibodies to the Cryptococcus neoformans capsular glucuronoxylomannan are ubiquitous in serum from HIV+ and HIV- individuals. Clin Exp Immunol. 1995;99:425–32.CrossRefGoogle Scholar
  30. 30.
    Abadi J, Pirofski L. Antibodies reactive with the cryptococcal capsular polysaccharide glucuronoxylomannan are present in sera from children with and without human immunodeficiency virus infection. J Infect Dis. 1999;180:915–9.CrossRefGoogle Scholar
  31. 31.
    •• Subramaniam K, Metzger B, Hanau LH, Guh A, Rucker L, Badri S, et al. IgM(+) memory B cell expression predicts HIV-associated cryptococcosis status. J Infect Dis. 2009;200:244–51 This paper shows that in a prospective and a retrospective cohort, levels of IgM memory B cells were lower in HIV-infected persons with than without a history of CM, suggesting the hypothesis that reduced levels of IgM memory B cells may portend risk for development of CM.CrossRefGoogle Scholar
  32. 32.
    Jalali Z, Ng L, Singh N, Pirofski LA. Antibody response to Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan in patients after solid-organ transplantation. Clin Vaccine Immunol. 2006;13:740–6.CrossRefGoogle Scholar
  33. 33.
    Carsetti R, Rosado MM, Wardmann H. Peripheral development of B cells in mouse and man. Immunol Rev. 2004;197:179–91.CrossRefGoogle Scholar
  34. 34.
    •• Rohatgi S, Nakouzi A, Carreno LJ, Slosar-Cheah M, Kuniholm MH, Wang T, et al. Antibody and B cell subset perturbations in human immunodeficiency virus-uninfected patients with cryptococcosis. Open Forum Infect Dis. 2018;5:ofx255.CrossRefGoogle Scholar
  35. 35.
    Jo EK, Kim HS, Lee MY, Iseki M, Lee JH, Song CH, et al. X-linked hyper-IgM syndrome associated with Cryptosporidium parvum and Cryptococcus neoformans infections: the first case with molecular diagnosis in Korea. J Korean Med Sci. 2002;17:116–20.CrossRefGoogle Scholar
  36. 36.
    Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226–33.CrossRefGoogle Scholar
  37. 37.
    Arthurs B, Wunderle K, Hsu M, Kim S. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia. Respir Med Case Rep. 2017;21:27–9.Google Scholar
  38. 38.
    Baron M, Zini JM, Challan Belval T, Vignon M, Denis B, Alanio A, et al. Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma. 2017;58:2981–2.CrossRefGoogle Scholar
  39. 39.
    Ruchlemer R, Ben Ami R, Lachish T. Ibrutinib for chronic lymphocytic leukemia. N Engl J Med. 2016;374:1593–4.Google Scholar
  40. 40.
    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;66:140–8.CrossRefGoogle Scholar
  41. 41.
    Messina JA, Maziarz EK, Spec A, Kontoyiannis DP, Perfect JR. Disseminated Cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib. Open Forum Infect Dis. 2017;4:ofw261.Google Scholar
  42. 42.
    Chiani P, Bromuro C, Cassone A, Torosantucci A. Anti-beta-glucan antibodies in healthy human subjects. Vaccine. 2009;27:513–9.CrossRefGoogle Scholar
  43. 43.
    Rodrigues ML, Travassos LR, Miranda KR, Franzen AJ, Rozental S, de Souza W, et al. Human antibodies against a purified glucosylceramide from Cryptococcus neoformans inhibit cell budding and fungal growth. Infect Immun. 2000;68:7049–60.CrossRefGoogle Scholar
  44. 44.
    •• Yoon HA, Nakouzi A, Chang CC, Kuniholm MH, Carreno LJ, Wang T, et al. Association between plasma antibody responses and risk for Cryptococcus-associated immune reconstitution inflammatory syndrome. J Infect Dis. 2018; This study shows plasma antibody profiles differ in HIV-infected patients with and without cryptococcal immune reconstitution inflammatory syndrome (C-IRIS), and that levels of of IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM are lower in patients with than without C-IRIS, suggesting these antibodies may play a role in controlling C-IRIS–associated inflammation.Google Scholar
  45. 45.
    Hlupeni A, Nakouzi A, Wang T, Boyd KF, Makadzange TA, Ndhlovu CE, et al. Antibody responses in HIV-infected patients with advanced immunosuppression and asymptomatic cryptococcal antigenemia. Open Forum Infect Dis. 2019;6:ofy333.CrossRefGoogle Scholar
  46. 46.
    Longley N, Jarvis JN, Meintjes G, Boulle A, Cross A, Kelly N, et al. Cryptococcal antigen screening in patients initiating ART in South Africa: a prospective cohort study. Clin Infect Dis. 2016;62:581–7.CrossRefGoogle Scholar
  47. 47.
    Rhein J, Bahr NC, Morawski BM, Schutz C, Zhang Y, Finkelman M, et al. Detection of high cerebrospinal fluid levels of (1-->3)-beta-d-glucan in cryptococcal meningitis. Open Forum Infect Dis. 2014;1:ofu105.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Nuria Trevijano-Contador
    • 1
  • Liise-anne Pirofski
    • 1
    • 2
    • 3
    Email author
  1. 1.Division of Infectious Diseases, Department of MedicineAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Microbiology & ImmunologyAlbert Einstein College of MedicineBronxUSA
  3. 3.Biomedical Research, Division of Infectious DiseasesAlbert Einstein College of Medicine & Montefiore Medical CenterBronxUSA

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