Project Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 4/6/23 → 3/31/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $737,302.00
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