Pathogenesis of Cryptococcal Meningoencephalitis in HIV-Infected Adults: Host-Pathogen Interactions, Fungal Tropism, and Novel Therapeutic Targets Identified in the Nigerian Population

Cryptococcal meningoencephalitis (CM) remains the most deadly fungal infection globally, with Nigeria bearing a disproportionate mortality burden among HIV-infected adults, yet host-pathogen interaction dynamics driving central nervous system tropism and poor treatment outcomes in Nigerian patients are insufficiently characterized. This integrative pathogenesis study enrolled 80 HIV-positive adults with confirmed CM at Lagos University Teaching Hospital and Federal Medical Centre Abuja across the South West and North Central geopolitical zones. Cerebrospinal fluid and blood samples were analyzed by whole-genome sequencing of clinical Cryptococcus neoformans isolates, flow cytometric immunophenotyping of CNS-infiltrating immune cells from CSF, Luminex-based CSF cytokine profiling, and proteomics analysis of CSF protein differences between early and late CM presentation. Cryptococcus neoformans MLST demonstrated VNI/VNII hybrid dominance at 78.8 percent, with ST5 most prevalent. Transcapsular antigen and laccase-encoding gene expression were significantly elevated in isolates from fatal cases. CSF immunophenotyping identified a CD4-depleted, PD-1-exhausted T cell environment that correlated with cryptococcal burden and mortality. Laccase activity correlated inversely with CSF IFN-gamma levels. CSF proteomics identified differential complement pathway depletion in fatal versus survivor cases. These integrated findings propose a host-pathogen interaction model centered on T cell exhaustion, complement evasion, and laccase-mediated immunosuppression as primary drivers of CM mortality in Nigerian HIV patients, identifying PD-1 blockade and complement pathway restoration as candidate adjunctive therapeutic targets. Keywords: Cryptococcal meningoencephalitis, HIV, host-pathogen interactions, Nigeria, therapeutic targets.