@article{1e4155c714194801831a4bb0e812c903,
title = "Macrophage cell death and transcriptional response are actively triggered by the fungal virulence factor Cbp1 during H. capsulatum infection",
abstract = "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 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 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 during H. capsulatum infection 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 in H. capsulatum pathogenesis.",
author = "Isaac, {Dervla T.} and Berkes, {Charlotte A.} and English, {Bevin C.} and {Hocking Murray}, Davina and Lee, {Young Nam} and Alison Coady and Anita Sil",
note = "Funding Information: We are grateful to Daniel Portnoy, Denise Monack, Jeffery Cox, Joseph DeRisi, Russell Vance, Charlie Kim, Sajeev Batra, Greg Barton, Allison Miller, Suzanne Noble and members of the Noble and Sil laboratories for useful discussion as this work progressed.We greatly appreciate the gift of mice from Vishva Dixit and Scott Oakes and the gift of macrophages from Denise Monack. We thank Johnny Tse for technical assistance. We thank Sinem Beyhan, Sarah Gilmore and Mark Voorhies for helpful comments on the manuscript. We appreciate the assistance of Jennifer Bolen of the UCSF Mouse Pathology Core facility for preparation of the tissue sections. We thank M. Paige Nittler, Katie Hermens, Sajeev Batra and the Bay Area Innate Immunity PO1 group for the production of MEEBO arrays. This work was supported by UCSF Immunology Training Grant (T32 AI07334) support to CAB and BCE; Microbial Pathogenesis and Host Defense Training Grant (NIH T32 A1060537) support to CAB, DTI and BCE; an NSF graduate research fellowship to AC; a UCSF NIGMS fellowship to DTI (1R25GM56847); an American Lung Association Senior Research Training Fellowship (RT- 195877-N) to YNL; NIH (R01AI066224 and PO1AI063302) and an HHMI Early Career Scientist Award (http:// www.hhmi.org/research/ecs/) to AS; the Sandler Program in Basic Sciences and the Howard Hughes Medical Institute Biomedical Research Support Program Grant (5300246) to the UCSF School of Medicine. Publisher Copyright: {\textcopyright} 2015 John Wiley & Sons Ltd.",
year = "2015",
month = dec,
day = "1",
doi = "10.1111/mmi.13168",
language = "English (US)",
volume = "98",
pages = "910--929",
journal = "Molecular Microbiology",
issn = "0950-382X",
publisher = "Wiley-Blackwell",
number = "5",
}