Macrophage cell death and transcriptional response are actively triggered by the fungal virulence factor Cbp1 duringH.capsulatuminfection

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Abstract

Summary

Microbial pathogens induce or inhibit death of host cells during infection, with significant consequences for virulence and disease progression. Death of an infected host cell can either facilitate release and dissemination of intracellular pathogens or promote pathogen clearance.Histoplasma capsulatumis an intracellular fungal pathogen that replicates robustly within macrophages and triggers macrophage lysis by unknown means. To identifyH.capsulatumeffectors of macrophage lysis, we performed a genetic screen and discovered three mutants that grew to wild-type levels within macrophages but failed to elicit host-cell death. Each mutant was defective in production of the previously identified secreted protein Cbp1 (calcium-binding protein 1), whose role in intracellular growth had not been fully investigated. We found that Cbp1 was dispensable for high levels of intracellular growth but required to elicit a unique transcriptional signature in macrophages, including genes whose induction was previously associated with endoplasmic reticulum stress and host-cell death. Additionally, Cbp1 was required for activation of cell-death caspases-3/7, and macrophage death duringH.capsulatuminfection was dependent on the pro-apoptotic proteins Bax and Bak. Taken together, these findings strongly suggest that the ability of Cbp1 to actively program host-cell death is an essential step inH.capsulatumpathogenesis.

We investigated the ability of the fungal pathogen Histoplasma capsulatum to infect macrophages, resulting in fungal replication and host-cell death. Genetic and molecular dissection of this process revealed that a fungal factor, Cbp1, is required to trigger a macrophage transcriptional response and host-cell death by apoptosis.

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