Macrophage cell death and transcriptional response are actively triggered by the fungal virulence factor C bp1 during H . capsulatum infection

• Published in: Molecular microbiology 2015-12, Vol.98 (5), p.910-929
• Main Authors: Isaac, Dervla T., Berkes, Charlotte A., English, Bevin C., Hocking Murray, Davina, Lee, Young Nam, Coady, Alison, Sil, Anita
• Format: Article
• Language: English
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.13168

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. H istoplasma capsulatum is an intracellular fungal pathogen that replicates robustly within macrophages and triggers macrophage lysis by unknown means. To identify H . capsulatum effectors 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 C bp1 (calcium‐binding protein 1), whose role in intracellular growth had not been fully investigated. We found that C bp1 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, C bp1 was required for activation of cell‐death caspases‐3/7, and macrophage death during H . capsulatum infection was dependent on the pro‐apoptotic proteins Bax and Bak. Taken together, these findings strongly suggest that the ability of C bp1 to actively program host‐cell death is an essential step in H . capsulatum pathogenesis.