| [PMID]: | 28953979 |
| [Au] Autor: | English BC; Van Prooyen N; Örd T; Örd T; Sil A |
| [Ad] Endereço: | Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America. |
| [Ti] Título: | The transcription factor CHOP, an effector of the integrated stress response, is required for host sensitivity to the fungal intracellular pathogen Histoplasma capsulatum. |
| [So] Source: | PLoS Pathog;13(9):e1006589, 2017 Sep. |
| [Is] ISSN: | 1553-7374 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | 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. |
| [Mh] Termos MeSH primário: |
Apoptose/imunologia
Genes Fúngicos/genética
Histoplasma/metabolismo
Histoplasmose/microbiologia
Macrófagos/metabolismo
Fator de Transcrição CHOP/metabolismo
|
| [Mh] Termos MeSH secundário: |
Animais
Proteínas de Ligação ao Cálcio/metabolismo
Células Cultivadas
Citoplasma/metabolismo
Feminino
Interações Hospedeiro-Patógeno/imunologia
Macrófagos/microbiologia
Camundongos
Virulência/genética
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Calcium-Binding Proteins); 147336-12-7 (Transcription Factor CHOP) |
| [Em] Mês de entrada: | 1711 |
| [Cu] Atualização por classe: | 171107 |
[Lr] Data última revisão:
| 171107 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170928 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1371/journal.ppat.1006589 |
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