Journal of Microbiology

, Volume 57, Issue 1, pp 45–53 | Cite as

Increased susceptibility against Cryptococcus neoformans of lupus mouse models (pristane-induction and FcGRIIb deficiency) is associated with activated macrophage, regardless of genetic background

  • Saowapha Surawut
  • Jiradej Makjaroen
  • Arthid Thim-uam
  • Jutamas Wongphoom
  • Tanapat Palaga
  • Prapaporn Pisitkun
  • Ariya Chindamporn
  • Asada LeelahavanichkulEmail author
Microbial Genetics, Genomics and Molecular Biology


The severity of cryptococcosis in lupus from varying genetic-backgrounds might be different due to the heterogeneity of lupus-pathogenesis. This study explored cryptococcosis in lupus mouse models of pristane-induction (normal genetic-background) and FcGRIIb deficiency (genetic defect). Because the severity of lupus nephritis, as determined by proteinuria and serum creatinine, between pristane and FcGRIIb-/- mice were similar at 6-month-old, Cryptococcus neoformans was intravenously administered in 6-month-old mice and were age-matched with wild-type. Indeed, the cryptococcosis disease severity, as evaluated by mortality rate, internal-organ fungal burdens and serum cytokines, between pristane and FcGRIIb-/- mice was not different. However, the severity of cryptococcosis in wild-type was less severe than the lupus mice. On the other hand, phagocytosis activity of peritoneal macrophages from lupus mice (pristane and FcGRIIb-/-) was more predominant than the wild-type without the difference in macrophage killing-activity among these groups. In addition, the number of active T helper cells (Th-cell) in the spleen, including Th-cells with intracellular IFN-γ, from lupus mice (pristane and FcGRIIb-/-) was higher than wildtype. Moreover, these active Th-cells were even higher after 2 weeks of cryptococcal infection. These data support enhanced macrophage activation through prominent Th-cells in both lupus models. In conclusion, an increased susceptibility of cryptococcosis in both lupus models was independent to genetic background. This might due to Th-cell enhanced macrophage phagocytosis with the interference of macrophage killing activity from Cryptococcal immune-evasion properties.


Cryptococcus neoformans pristane model FcGRIIb deficient mice lupus susceptibility murine model 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

12275_2019_8311_MOESM1_ESM.pdf (802 kb)
Supplementary material, approximately 802 KB.


  1. Bermas, B.L., Petri, M., Goldman, D., Mittleman, B., Miller, M.W., Stocks, N.I., Via, C.S., and Shearer, G.M. 1994. T helper cell dysfunction in systemic lupus erythematosus (SLE): relation to disease activity. J. Clin. Immunol. 14, 169–177.CrossRefGoogle Scholar
  2. Bolland, S. and Ravetch, J.V. 2000. Spontaneous autoimmune disease in FcγRIIB-deficient mice results from strain-specific epistasis. Immunity 13, 277–285.CrossRefGoogle Scholar
  3. Buchanan, K.L. and Doyle, H.A. 2000. Requirement for CD4+ T lymphocytes in host resistance against Cryptococcus neoformans in the central nervous system of immunized mice. Infect. Immun. 68, 456–462.CrossRefGoogle Scholar
  4. Charlier, C., Nielsen, K., Daou, S., Brigitte, M., Chretien, F., and Dromer, F. 2009. Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans. Infect. Immun. 77, 120–127.CrossRefGoogle Scholar
  5. Chen, H.S., Tsai, W.P., Leu, H.S., Ho, H.H., and Liou, L.B. 2007. Invasive fungal infection in systemic lupus erythematosus: an analysis of 15 cases and a literature review. Rheumatology (Oxford) 46, 539–544.CrossRefGoogle Scholar
  6. Clatworthy, M.R., Willcocks, L., Urban, B., Langhorne, J., Williams, T.N., Peshu, N., Watkins, N.A., Floto, R.A., and Smith, K.G. 2007. Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria. Proc. Natl. Acad. Sci. USA 104, 7169–7174.CrossRefGoogle Scholar
  7. Crispin, J.C., Hedrich, C.M., and Tsokos, G.C. 2013. Gene-function studies in systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 476–484.CrossRefGoogle Scholar
  8. Garcia-Rodas, R. and Zaragoza, O. 2012. Catch me if you can: phagocytosis and killing avoidance by Cryptococcus neoformans. FEMS Immunol. Med. Microbiol. 64, 147–161.CrossRefGoogle Scholar
  9. Hu, X.P., Wu, J.Q., Zhu, L.P., Wang, X., Xu, B., Wang, R.Y., Ou, X.T., and Weng, X.H. 2012. Association of Fcγ receptor IIB polymorphism with cryptococcal meningitis in HIV-uninfected Chinese patients. PLoS One 7, e42439.CrossRefGoogle Scholar
  10. Kasagi, S., Kawano, S., Okazaki, T., Honjo, T., Morinobu, A., Hatachi, S., Shimatani, K., Tanaka, Y., Minato, N., and Kumagai, S. 2010. Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice. J. Immunol. 184, 2337–2347.CrossRefGoogle Scholar
  11. Koguchi, Y. and Kawakami, K. 2002. Cryptococcal infection and Th1-Th2 cytokine balance. Int. Rev. Immunol. 21, 423–438.CrossRefGoogle Scholar
  12. Leiss, H., Niederreiter, B., Bandur, T., Schwarzecker, B., Bluml, S., Steiner, G., Ulrich, W., Smolen, J.S., and Stummvoll, G.H. 2013. Pristane-induced lupus as a model of human lupus arthritis: evolvement of autoantibodies, internal organ and joint inflammation. Lupus 22, 778–792.CrossRefGoogle Scholar
  13. Li, Q., You, C., Liu, Q., and Liu, Y. 2010. Central nervous system cryptococcoma in immunocompetent patients: a short review illustrated by a new case. Acta Neurochir. (Wien) 152, 129–136.CrossRefGoogle Scholar
  14. Liu, T.B., Perlin, D.S., and Xue, C. 2012. Molecular mechanisms of cryptococcal meningitis. Virulence 3, 173–181.CrossRefGoogle Scholar
  15. Maglione, P.J., Xu, J., Casadevall, A., and Chan, J. 2008. Fcγ receptors regulate immune activation and susceptibility during Mycobacterium tuberculosis infection. J. Immunol. 180, 3329–3338.CrossRefGoogle Scholar
  16. Mody, C.H., Lipscomb, M.F., Street, N.E., and Toews, G.B. 1990. Depletion of CD4+ (L3T4+) lymphocytes in vivo impairs murine host defense to Cryptococcus neoformans. J. Immunol. 144, 1472–1477.Google Scholar
  17. Ngamskulrungroj, P., Chang, Y., Sionov, E., and Kwon-Chung, K.J. 2012. The primary target organ of Cryptococcus gattii is different from that of Cryptococcus neoformans in a murine model. MBio 3, e00103–12.CrossRefGoogle Scholar
  18. Nicola, A.M. and Casadevall, A. 2012. In vitro measurement of phagocytosis and killing of Cryptococcus neoformans by macrophages. Methods Mol. Biol. 844, 189–197.CrossRefGoogle Scholar
  19. Ondee, T., Surawut, S., Taratummarat, S., Hirankarn, N., Palaga, T., Pisitkun, P., Pisitkun, T., and Leelahavanichkul, A. 2017. Fc gamma receptor IIB deficient mice: A lupus model with increased endotoxin tolerance-related sepsis susceptibility. Shock 47, 743–752.CrossRefGoogle Scholar
  20. Ray, A. and Dittel, B.N. 2010. Isolation of mouse peritoneal cavity cells. J. Vis. Exp. 35 1488.Google Scholar
  21. Reeves, W.H., Lee, P.Y., Weinstein, J.S., Satoh, M., and Lu, L. 2009. Induction of autoimmunity by pristane and other naturally occurring hydrocarbons. Trends Immunol. 30, 455–464.CrossRefGoogle Scholar
  22. Rohatgi, S. and Pirofski, L.A. 2015. Host immunity to Cryptococcus neoformans. Future Microbiol. 10, 565–581.CrossRefGoogle Scholar
  23. Romani, L. 2004. Immunity to fungal infections. Nat. Rev. Immunol. 4, 1–23.CrossRefGoogle Scholar
  24. Ropes, M.W. 1964. Observations on the natural course of disseminated lupus erythematosus. Medicine (Baltimore) 43, 387–391.CrossRefGoogle Scholar
  25. Rottman, J.B. and Willis, C.R. 2010. Mouse models of systemic lupus erythematosus reveal a complex pathogenesis. Vet. Pathol. 47, 664–676.CrossRefGoogle Scholar
  26. Satoh, M., Kumar, A., Kanwar, Y.S., and Reeves, W.H. 1995. Antinuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane. Proc. Natl. Acad. Sci. USA 92, 10934–10938.CrossRefGoogle Scholar
  27. Satoh, M. and Reeves, W.H. 1994. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J. Exp. Med. 180, 2341–2346.CrossRefGoogle Scholar
  28. Smith, K.G. and Clatworthy, M.R. 2010. FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat. Rev. Immunol. 10, 328–343.CrossRefGoogle Scholar
  29. Surawut, S., Ondee, T., Taratummarat, S., Palaga, T., Pisitkun, P., Chindamporn, A., and Leelahavanichkul, A. 2017. The role of macrophages in the susceptibility of Fc gamma receptor IIb deficient mice to Cryptococcus neoformans. Sci. Rep. 7, 40006.CrossRefGoogle Scholar
  30. Tsokos, G.C. 2011. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121.CrossRefGoogle Scholar
  31. Vonk, A.G., Wieland, C.W., Netea, M.G., and Kullberg, B.J. 2002. Phagocytosis and intracellular killing of Candida albicans blastoconidia by neutrophils and macrophages: a comparison of different microbiological test systems. J. Microbiol. Methods 49, 55–62.CrossRefGoogle Scholar
  32. Walenkamp, A.M., Scharringa, J., Schramel, F.M., Coenjaerts, F.E., and Hoepelman, I.M. 2000. Quantitative analysis of phagocytosis of Cryptococcus neoformans by adherent phagocytic cells by fluorescence multi-well plate reader. J. Microbiol. Methods 40, 39–45.CrossRefGoogle Scholar
  33. Wang, L.R., Barber, C.E., Johnson, A.S., and Barnabe, C. 2014. Invasive fungal disease in systemic lupus erythematosus: a systematic review of disease characteristics, risk factors, and prognosis. Semin. Arthritis Rheum. 44, 325–330.CrossRefGoogle Scholar
  34. Zandman-Goddard, G. and Shoenfeld, Y. 2005. Infections and SLE. Autoimmunity 38, 473–485.CrossRefGoogle Scholar
  35. Zhong, Y., Li, M., Liu, J., Zhang, W., and Peng, F. 2015. Cryptococcal meningitis in Chinese patients with systemic lupus erythematosus. Clin. Neurol. Neurosurg. 131, 59–63.CrossRefGoogle Scholar

Copyright information

© The Microbiological Society of Korea and Springer Nature B.V. 2019

Authors and Affiliations

  • Saowapha Surawut
    • 1
  • Jiradej Makjaroen
    • 1
  • Arthid Thim-uam
    • 2
  • Jutamas Wongphoom
    • 3
  • Tanapat Palaga
    • 4
  • Prapaporn Pisitkun
    • 5
  • Ariya Chindamporn
    • 6
  • Asada Leelahavanichkul
    • 6
    • 7
    Email author
  1. 1.Medical Microbiology, Interdisciplinary Program, Graduate SchoolChulalongkorn UniversityBangkokThailand
  2. 2.Inter-Department Program of Biomedical Sciences, Faculty of GraduateChulalongkorn UniversityBangkokThailand
  3. 3.Division of Pathology, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  4. 4.Department of Microbiology, Faculty of ScienceChulalongkorn UniversityBangkokThailand
  5. 5.Division of Allergy, Immunology and Rheumatology, Department of Medicine, Ramathibodi HospitalMahidol UniversityBangkokThailand
  6. 6.Department of Microbiology, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  7. 7.Skeletal Disorders Research Unit, Faculty of DentistryChulalongkorn UniversityBangkokThailand

Personalised recommendations