Macrophage cell death and transcriptional response are actively triggered by the fungal virulence factor Cbp1 during H. capsulatum infection.
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.
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.
Dervla T
DT
Isaac
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.|Department of Biology, Merrimack College, North Andover, MA.
Charlotte A
CA
Berkes
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.
Bevin C
BC
English
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.
Davina Hocking
DH
Murray
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.
Young Nam
YN
Lee
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.
Alison
A
Coady
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143-0414.|Howard Hughes Medical Institute, San Francisco, CA.
Anita
A
Sil
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005800:Genes, Fungal; D016681:Genome, Fungal; D006658:Histoplasma / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D006660:Histoplasmosis / Q000382:microbiology*; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D002135:Calcium-Binding Proteins; C416373:Cbp1 protein, histoplasma; D037521:Virulence Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020169:Caspases