Differential recognition of C. neoformans by male and female human macrophages elicits contrasting immune responses

Cryptococcus neoformans (Cn) is a pathogenic yeast and the cause of cryptococcosis, a life-threatening fungal disease. Strikingly, ~70% of patients that develop cryptococcosis are male. Here, we investigated decreased Cn recognition by male macrophages and the impact on the subsequent innate immune response. Human PBMCs were isolated from healthy male and female donors, differentiated into macrophages, and tested for immune response differences. Cn incubated with female serum showed increased binding of the opsonin serum amyloid P component, possibly explaining the increased Cn phagocytosis in female macrophages. Cytokine analysis showed increased secretion of proinflammatory cytokines at 24 h in male macrophages that substantially decreased by 48 h. In contrast, female macrophages secreted fewer proinflammatory cytokines at both 24 and 48 h but had increased secretion of CCL5 (24 and 48 h) and IL-18 (48 h). As male macrophages rapidly downregulated proinflammatory immune responses after 24 h; we investigated the macrophage activation state. Male macrophages were alternatively activated at 48 h, with increased secretion of arginase 1 whereas female macrophages were classically activated, with increased secretion of nitric oxide at 24 and 48 h. Cn genes related to glucuronoxylomannan (GXM) biosynthesis were increased in Cn grown in male serum at 48 h. These data suggest that female macrophages better recognize Cn and become classically activated whereas male macrophages initiate an inflammatory response that is markedly reduced after 24 h, possibly due to testosterone-induced GXM secretion. Therefore, antifungal therapeutics targeting testosterone-induced GXM release may improve outcomes in male patients with cryptococcosis.