ArticlePLoS pathogens2017
The transcription factor CHOP, an effector of the integrated stress response, is required for host sensitivity to the fungal intracellular pathogen Histoplasma capsulatum.
Article in PLoS pathogens, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 33 citations in OpenAlex.
- GRP78 dysregulation: A proposed molecular mechanism linking the tumor microenvironment to sepsis susceptibility in patients with cancer (Review).International journal of molecular medicine · 2026Review
- The Rpd3 histone deacetylase is a critical regulator of temperature-mediated morphogenesis and virulence in the human fungal pathogen Histoplasma.PLoS biology · 2026Article
- How Histoplasma Evades the Human Immune System.Acta medica academica · 2025Review
- Article
- Genotypic diversity, virulence, and molecular genetic tools inMicrobiology and molecular biology reviews : MMBR · 2024Review
- Common virulence factors betweenCurrent research in microbial sciences · 2024Review
- Stress granules: potential therapeutic targets for infectious and inflammatory diseases.Frontiers in immunology · 2023Review
- Pathogenicity & virulence ofVirulence · 2022Review
- Inflammatory Mechanism ofInternational journal of molecular sciences · 2022Review
- Genome-scale CRISPR screening reveals that C3aR signaling is critical for rapid capture of fungi by macrophages.PLoS pathogens · 2022Article
- Cbp1, a fungal virulence factor under positive selection, forms an effector complex that drives macrophage lysis.PLoS pathogens · 2022Article
- Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection.PLoS neglected tropical diseases · 2022Article
- Hiding in Plain Sight: Formation and Function of Stress Granules During Microbial Infection of Mammalian Cells.Frontiers in molecular biosciences · 2021Review
- BiodiversemSphere · 2020Article
- C. sakazakii activates AIM2 pathway accompanying with excessive ER stress response in mammalian mammary gland epithelium.Cell stress & chaperones · 2020Article
- TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription.Nature communications · 2019Article
- Sensing the heat and the host: Virulence determinants ofVirulence · 2019Review
- Opposing signaling pathways regulate morphology in response to temperature in the fungal pathogen Histoplasma capsulatum.PLoS biology · 2019Article
- Article
- Histoplasma Capsulatum: Mechanisms for Pathogenesis.Current topics in microbiology and immunology · 2019Review
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The ability of intracellular pathogens to manipulate host-cell viability is critical to successful infection. Some pathogens promote host-cell survival to protect their replicative niche, whereas others trigger host-cell death to facilitate release and dissemination of the pathogen after intracellular replication has occurred. We previously showed that the intracellular fungal pathogen Histoplasma capsulatum (Hc) uses the secreted protein Cbp1 to actively induce apoptosis in macrophages; interestingly, cbp1 mutant strains are unable to kill macrophages and display severely reduced virulence in the mouse model of Hc infection. To elucidate the mechanism of Cbp1-induced host-cell death, we performed a comprehensive alanine scanning mutagenesis and identified all amino acid residues that are required for Cbp1 to trigger macrophage lysis. Here we demonstrate that Hc strains expressing lytic CBP1 alleles activate the integrated stress response (ISR) in infected macrophages, as indicated by an increase in eIF2α phosphorylation as well as induction of the transcription factor CHOP and the pseudokinase Tribbles 3 (TRIB3). In contrast, strains bearing a non-lytic allele of CBP1 fail to activate the ISR, whereas a partially lytic CBP1 allele triggers intermediate levels of activation. We further show that macrophages deficient for CHOP or TRIB3 are partially resistant to lysis during Hc infection, indicating that the ISR is critical for susceptibility to Hc-mediated cell death. Moreover, we show that CHOP-dependent macrophage lysis is critical for efficient spread of Hc infection to other macrophages. Notably, CHOP knockout mice display reduced macrophage apoptosis and diminished fungal burden and are markedly resistant to Hc infection. Together, these data indicate that Cbp1 is required for Hc to induce the ISR and mediate a CHOP-dependent virulence pathway in the host.
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