Abstract
Cryptococcus neoformans is an opportunistic yeast that kills over 625,000 people yearly through lethal meningitis. Host phagocytes serve as the first line of defense against this pathogen, but fungal engulfment and subsequent intracellular proliferation also correlate with poor patient outcome. Defining the interactions of this facultative intracellular pathogen with host phagocytes is key to understanding the latter’s opposing roles in infection and how they contribute to fungal latency, dissemination, and virulence. We used high-content imaging and a human monocytic cell line to screen 1,201 fungal mutants for strains with altered host interactions and identified multiple genes that influence fungal adherence and phagocytosis. One of these genes was PFA4, which encodes a protein S-acyl transferase (PAT), one of a family of DHHC domain-containing proteins that catalyzes lipid modification of proteins. Deletion of PFA4 caused dramatic defects in cryptococcal morphology, stress tolerance, and virulence. Bioorthogonal palmitoylome-profiling identified Pfa4-specific protein substrates involved in cell wall synthesis, signal transduction, and membrane trafficking responsible for these phenotypic alterations. We demonstrate that a single PAT is responsible for the modification of a subset of proteins that are critical in cryptococcal pathogenesis. Since several of these palmitoylated substrates are conserved in other pathogenic fungi, protein palmitoylation represents a potential avenue for new antifungal therapeutics.
Highlights
Cryptococcus neoformans is a fungal pathogen that causes over 625,000 deaths per year, mainly in severely immunocompromised individuals
In immunocompromised people, the initial lung infection can spread to other sites, to the central nervous system
Our studies demonstrate that a single protein S-acyl transferase (PAT) is a major determinant of cryptococcal pathogenesis and, by defining the relevant palmitoylome, we identify the cellular mechanisms by which defects of this fatty acid modification dramatically alter fungal morphology, host interactions, and virulence in vivo
Summary
Cryptococcus neoformans is a fungal pathogen that causes over 625,000 deaths per year, mainly in severely immunocompromised individuals. Cryptococcosis is contracted by inhalation of infectious particles from the environment [1], which leads to a primary pulmonary infection In healthy people this infection is typically cleared, but in immunocompromised hosts the organism can proliferate and disseminate, with a tropism for the central nervous system where it causes lethal meningoencephalitis. As a result, this pathogen is a major threat to AIDS patients and to the rapidly growing population of individuals with other immunosuppressive conditions [2,3,4,5]. Despite the importance of these interactions to cryptococcal pathogenesis, the critical features of the host and fungus that govern them have not been determined
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