Continuum of Immune Responses to Cryptococcus neoformans

Abstract Cryptococcal meningitis (CM), caused by the fungal pathogen Cryptococcus neoformans (Cn), is among the most prevalent HIV/AIDS-associated opportunistic infections and causes 15% of AIDS- related mortality globally. In healthy individuals, exposure to Cn in early childhood results in a pulmonary latent infection that is asymptomatic, but leads to the formation of lung granulomas. Following HIV-associated compromise of the immune system, control of latent Cn infection within pulmonary granulomas is lost and the fungus disseminates to cause meningitis. Most studies examining host-pathogen interactions in Cn are observational studies in human cohorts or analyze reference Cn strains in acute disease models of cryptococcosis. We recently showed that the mouse model accurately recapitulates differences in human survival that are observed across Cn clinical isolates and used these data to develop a mouse model of latent Cn infection. Our preliminary data using these mouse models to analyze the immune response to over 50 Cn clinical isolates from individuals with advanced HIV revealed a continuum of disease outcomes that we classified into 3 groups: 1) latent infection resulting in granuloma formation and control; 2) lethal disease similar to that observed with Cn reference strains; and 3) hypervirulence resulting in rapid mortality. Previous studies with reference strains revealed lethal disease is associated with various Cn virulence factors and a detrimental host Th2-mediated type-2 immune response. In contrast, disease prevention is associated with the type-1 cytokine IFNγ. How these Cn-host interactions differ to cause the continuum of disease observed in immunocompromised individuals with HIV is not well defined. We will use analysis of clinical isolates in mouse models of disease to test our central hypothesis that antigenic differences between Cn clinical isolates lead to either protective or detrimental immune responses in the host. We will test this hypothesis by pursuing three specific aims. Our first and second aims will determine the host cellular and effector functions that result in either latency (Aim 1), lethal disease (control infections), or hypervirulence (Aim 2). Our third aim will identify Cn gene alleles for antigens that influence the immune response and ultimately disease outcome. Taken together, these translational studies will define the molecular processes underlying the continuum of Cryptococcus disease with the goal of developing novel immune-modulatory treatment strategies for at-risk patient populations.