A CHARACTERISATION OF THE PATHOGENIC MECHANISMS DRIVING NEUROLOGICAL INJURY DURING <EM>CRYPTOCOCCUS GATTII </EM>INFECTION

Cryptococcal meningitis (CM) is a fatal fungal infection of the brain, associated with severe neurological damage. CM has traditionally been associated with immunocompromised individuals; however, rising global temperatures have been linked to an increasing incidence of CM in immunocompetent hosts, driven by emergence of Cryptococcus gattii. However, the mechanisms underlying its pathogenesis remain poorly defined. We addressed this gap by characterising the neuropathogenesis of C. gattii-related CM. Male and female C57BL/6 mice (8-10 weeks old) were intravenously infected with 5x10⁴ colony forming units of a fluorescent reporter strain of C. gattii (R265). We monitored disease progression by measuring fungal burden, body mass gain and survival rates. Histological analysis was performed on 1, 3, 6 days post-infection (dpi) and at experimental endpoint to assess neuropathological damage. Neuroinflammation was visualised using fluorescent labelling of nuclear factor for interlukin-6, and brain and serum cytokines measured using multiplex assays. Fungal invasion of the brain was detected as early as 1 dpi, followed by slow intracerebral replication culminating in peak fungal burdens at 25 dpi. Progressive increases in lesion number and size were observed with advancing disease. Body weight increased until 18 dpi before declining toward experimental endpoints. Mortality rates differed significantly between sexes, with males exhibiting higher mortality (64%) than females (33%) following C. gattii infection. Late-stage neuropathology was characterised by robust inflammatory cell accumulation surrounding cryptococcal lesions, accompanied by distinct temporal and sex-dependent cytokine profiles. Collectively, this data highlights marked temporal and sex-specific differences in the pathogenesis of C. gattii–associated cryptococcal meningitis.