Allelic Variation in CNAG_04922 Gene Modulates Host Cytokine Responses during Cryptococcus neoformans Infection

Cryptococcal meningitis (CM) remains a leading cause of mortality among people living with HIV, particularly in sub-Saharan Africa, despite increased access to antiretroviral therapy. Host-pathogen interactions are crucial in determining CM outcomes, with immune status and fungal genetic variation influencing disease severity. This study investigated how allelic variation in the CNAG_04922 gene of Cryptococcus neoformans modulates host immune responses, using ex vivo cytokine profiling. Peripheral blood samples from HIV-positive and HIV-negative adults were stimulated with heat-inactivated whole-cell antigens from strains carrying either the CNAG_04922 reference allele (H99) or an alternate allele (UgCl377). Cytokine concentrations were quantified using Luminex assays. The H99 strain induced significantly higher levels of key cytokines—including CD40-ligand (p = 0.047), IL-10 (p = 0.028), IL-12p70 (p < 0.001), IL-13 (p < 0.001), IL-15 (p = 0.009), and IL-33 (p = 0.006)—suggesting a strong pro-inflammatory and regulatory immune response. Conversely, the CNAG_04922 alternate allele elicited a dampened cytokine profile, possibly enabling immune evasion. These findings support prior evidence that fungal genotypes shape host immunity and may influence disease outcomes. This study underscores the need for integrating fungal genotyping into CM management and highlights cytokine targets for therapeutic modulation.