Compartmentalization of innate immune responses in the central nervous system during cryptococcal meningitis/HIV coinfection

Objective: The role of innate immunity in the pathogenesis of cryptococcal meningitis is unclear. We hypothesized that natural killer (NK) cell and monocyte responses show central nervous system (CNS) compartment-specific profiles, and are altered by antifungal therapy and combination antiretroviral therapy (cART) during cryptococcal meningitis/HIV coinfection. Design: Substudy of a prospective cohort study of adults with cryptococcal meningitis/HIV coinfection in Durban, South Africa. Methods: We used multiparametric flow cytometry to study compartmentalization of subsets, CD69 (a marker of activation), CXCR3 and CX3CR1 expression, and cytokine secretion of NK cells and monocytes in freshly collected blood and cerebrospinal fluid (CSF) at diagnosis (n=23), completion of antifungal therapy induction (n=19), and after a further 4 weeks of cART (n=9). Results: Relative to blood, CSF was enriched with CD56^bright (immunoregulatory) NK cells (P=0.0004). At enrolment, CXCR3 expression was more frequent among blood CD56^bright than either blood CD56dim (P<0.0001) or CSF CD56^bright (P=0.0002) NK cells. Antifungal therapy diminished blood (P<0.05), but not CSF CXCR3^pos NK-cell proportions nor CX3CR1pos NK-cell proportions. CD56^bright and CD56^dim NK cells were more activated in CSF than blood (P<0.0001). Antifungal therapy induction reduced CD56^dim NK-cell activation in CSF (P=0.02). Activation of blood CD56^bright and CD56^dim NK cells was diminished following cART commencement (P<0.0001, P=0.03). Immunoregulatory NK cells in CSF tended to secrete higher levels of CXCL10 (P=0.06) and lower levels of tumor necrosis factor a (P=0.06) than blood immunoregulatory NK cells. CSF was enriched with nonclassical monocytes (P=0.001), but antifungal therapy restored proportions of classical monocytes (P=0.007).