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Ex Vivo Cytokine Profiling of Cryptococcus neoformans Strains Suggests Strain-Specific Immune Modulation: A
Kennedy Kassaza1, Fredrickson B Wasswa1, Kirsten Nielsen2
1Department of Microbiology and Parasitology, Mbarara University of Science and Technology, Mbarara, UGA.
Abstract:
Cryptococcal meningitis (CM) remains a major cause of mortality among people living with human immunodeficiency virus (HIV), especially in sub-Saharan Africa. The interplay between fungal genotype and host immune response is critical in determining disease outcome. We conducted ex vivo cytokine profiling using peripheral blood from HIV-positive and HIV-negative adults stimulated with heat-inactivated whole-cell antigens from two Cryptococcus neoformans strains: the reference strain H99 and the genetically distinct UgCl377 clinical strain. These strains differ at multiple loci, including the CNAG_04922 gene. Luminex-based quantification revealed that H99 induced significantly higher levels of CD40-ligand, IL-10, IL-12p70, IL-13, IL-15, and IL-33. These cytokines reflect pro-inflammatory, Th2, and regulatory responses, suggesting robust immune activation. In contrast, the UgCl377 strain elicited a dampened cytokine profile. While this study does not isolate the effect of CNAG_04922 alone, it demonstrates that whole-cell antigens from genetically distinct strains of C. neoformans elicit differential cytokine responses. These findings provide a foundation for future mechanistic studies using purified proteins or isogenic strains.
Insights
Cryptococcal meningitis (CM) in HIV patients is deadly. Genetically distinct Cryptococcus neoformans strains trigger different immune responses, impacting disease outcomes.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcal meningitis (CM) is a leading cause of death in people with human immunodeficiency virus (HIV), particularly in sub-Saharan Africa.
- Host immune response and fungal genotype significantly influence CM disease progression and outcomes.
Purpose of the Study:
- To investigate the differential ex vivo cytokine responses induced by two distinct Cryptococcus neoformans strains (H99 and UgCl377) in HIV-positive and HIV-negative adults.
- To explore the impact of fungal genetic variation on host immune activation in the context of cryptococcal infections.
Main Methods:
- Ex vivo cytokine profiling of peripheral blood from adults stimulated with heat-inactivated whole-cell antigens from C. neoformans strains H99 and UgCl377.
- Luminex-based quantification of various cytokines, including CD40-ligand, IL-10, IL-12p70, IL-13, IL-15, and IL-33.
Main Results:
- The reference strain H99 induced significantly higher levels of pro-inflammatory, Th2, and regulatory cytokines (CD40-ligand, IL-10, IL-12p70, IL-13, IL-15, IL-33), indicating robust immune activation.
- The genetically distinct clinical strain UgCl377 elicited a comparatively dampened cytokine profile.
- Differential cytokine responses were observed between the two C. neoformans strains, suggesting strain-specific immune modulation.
Conclusions:
- Whole-cell antigens from genetically distinct C. neoformans strains induce differential host cytokine responses.
- These findings highlight the importance of fungal genotype in shaping the immune landscape during cryptococcal meningitis.
- Provides a basis for future studies on specific fungal components and their role in immune evasion or activation.
