Abstract: Opportunistic CNS invasion by eukaryotic pathogens requires a highly coordinated, yet restrained, multi- pronged immune response. CNS Infection by extracellular parasites such as Naegleria fowleri, Acanthamoeba, and Balamuthia have proven nearly impossible to treat, yet immune directed therapies against N. fowleri have the potential alter the course of almost universally fatal disease. The “brain eating amoeba” N. fowleri is responsible for a devastating form of meningoencephalitis known as primary amoebic meningoencephalitis (PAM) that is almost universally fatal (>97%) despite intensive clinical intervention, and new therapeutic approaches are desperately needed. The protective relevance of Naegleria-reactive antibodies (Abs) in humans is unclear, but animal models of PAM suggest that vaccinations and passive Ab administration variably delay death and foster survival. Extracellular parasites cannot simply be neutralized by antibody, but rather immunity relies on targeting antibody isotype specific effector mechanisms from immune cells. After parasites are bound by antibody, isotype specific binding to fragment crystallizable receptors (FcRs) can direct cell type specific effector functions against parasites. Prior studies of N. fowleri specific antibody responses have not rigorously linked antibody specificity with the functional outcomes of individual\antibody isotypes, creating a critical gap in understanding how antibody can optimally eliminate parasites from the within the central nervous system (CNS) while not exacerbating immunopathology. We’ve generated a monoclonal Ab specific for N. fowleri cell surface antigens that has shown strong anti-proliferative effects on parasites in vitro and facilitates survival of infected hosts in vivo. This proposal seeks to define how combining anti-proliferative effects of antibody and isotype specific binding can facilitate effective immune response against extracellular CNS parasites while maintaining neuroprotection. Completion of this project will define new therapeutic approaches to CNS infections that currently have few effective options and very poor outcomes.