Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture

ABSTRACT Interferon-regulated immune defenses protect mammals from pathogenically diverse obligate intracellular bacterial pathogens of the genus Chlamydia. Interferon gamma (IFN-γ) is especially important in controlling the virulence of Chlamydia species and thus impacts the modeling of human chlam...

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Autores principales:	Amanda M. Giebel, Shuai Hu, Krithika Rajaram, Ryan Finethy, Evelyn Toh, Julie A. Brothwell, Sandra G. Morrison, Robert J. Suchland, Barry D. Stein, Jörn Coers, Richard P. Morrison, David E. Nelson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Chlamydia host-pathogen interactions interferon-stimulated genes intracellular pathogens molecular genetics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e8a90bbcb71f4e98a83cb61cb313a9e4
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spelling	oai:doaj.org-article:e8a90bbcb71f4e98a83cb61cb313a9e42021-11-15T15:55:25ZGenetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture10.1128/mBio.00385-192150-7511https://doaj.org/article/e8a90bbcb71f4e98a83cb61cb313a9e42019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00385-19https://doaj.org/toc/2150-7511ABSTRACT Interferon-regulated immune defenses protect mammals from pathogenically diverse obligate intracellular bacterial pathogens of the genus Chlamydia. Interferon gamma (IFN-γ) is especially important in controlling the virulence of Chlamydia species and thus impacts the modeling of human chlamydial infection and disease in mice. How IFN-γ contributes to cell-autonomous defenses against Chlamydia species and how these pathogens evade IFN-γ-mediated immunity in their natural hosts are not well understood. We conducted a genetic screen which identified 31 IFN-γ-sensitive (Igs) mutants of the mouse model pathogen Chlamydia muridarum. Genetic suppressor analysis and lateral gene transfer were used to map the phenotype of one of these mutants, Igs4, to a missense mutation in a putative chlamydial inclusion membrane protein, TC0574. We observed the lytic destruction of Igs4-occupied inclusions and accompanying host cell death in response to IFN-γ priming or various proapoptotic stimuli. However, Igs4 was insensitive to IFN-γ-regulated cell-autonomous defenses previously implicated in anti-Chlamydia trachomatis host defense in mice. Igs4 inclusion integrity was restored by caspase inhibitors, indicating that the IFN-γ-mediated destruction of Igs4 inclusions is dependent upon the function of caspases or related prodeath cysteine proteases. We further demonstrated that the Igs4 mutant is immune restricted in an IFN-γ-dependent manner in a mouse infection model, thereby implicating IFN-γ-mediated inclusion destruction and host cell death as potent in vivo host defense mechanisms to which wild-type C. muridarum is resistant. Overall, our results suggest that C. muridarum evolved resistance mechanisms to counter IFN-γ-elicited programmed cell death and the associated destruction of intravacuolar pathogens. IMPORTANCE Multiple obligatory intracellular bacteria in the genus Chlamydia are important pathogens. In humans, strains of C. trachomatis cause trachoma, chlamydia, and lymphogranuloma venereum. These diseases are all associated with extended courses of infection and reinfection that likely reflect the ability of chlamydiae to evade various aspects of host immune responses. Interferon-stimulated genes, driven in part by the cytokine interferon gamma, restrict the host range of various Chlamydia species, but how these pathogens evade interferon-stimulated genes in their definitive host is poorly understood. Various Chlamydia species can inhibit death of their host cells and may have evolved this strategy to evade prodeath signals elicited by host immune responses. We present evidence that chlamydia-induced programmed cell death resistance evolved to counter interferon- and immune-mediated killing of Chlamydia-infected cells.Amanda M. GiebelShuai HuKrithika RajaramRyan FinethyEvelyn TohJulie A. BrothwellSandra G. MorrisonRobert J. SuchlandBarry D. SteinJörn CoersRichard P. MorrisonDavid E. NelsonAmerican Society for MicrobiologyarticleChlamydiahost-pathogen interactionsinterferon-stimulated genesintracellular pathogensmolecular geneticsMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chlamydia host-pathogen interactions interferon-stimulated genes intracellular pathogens molecular genetics Microbiology QR1-502
spellingShingle	Chlamydia host-pathogen interactions interferon-stimulated genes intracellular pathogens molecular genetics Microbiology QR1-502 Amanda M. Giebel Shuai Hu Krithika Rajaram Ryan Finethy Evelyn Toh Julie A. Brothwell Sandra G. Morrison Robert J. Suchland Barry D. Stein Jörn Coers Richard P. Morrison David E. Nelson Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture
description	ABSTRACT Interferon-regulated immune defenses protect mammals from pathogenically diverse obligate intracellular bacterial pathogens of the genus Chlamydia. Interferon gamma (IFN-γ) is especially important in controlling the virulence of Chlamydia species and thus impacts the modeling of human chlamydial infection and disease in mice. How IFN-γ contributes to cell-autonomous defenses against Chlamydia species and how these pathogens evade IFN-γ-mediated immunity in their natural hosts are not well understood. We conducted a genetic screen which identified 31 IFN-γ-sensitive (Igs) mutants of the mouse model pathogen Chlamydia muridarum. Genetic suppressor analysis and lateral gene transfer were used to map the phenotype of one of these mutants, Igs4, to a missense mutation in a putative chlamydial inclusion membrane protein, TC0574. We observed the lytic destruction of Igs4-occupied inclusions and accompanying host cell death in response to IFN-γ priming or various proapoptotic stimuli. However, Igs4 was insensitive to IFN-γ-regulated cell-autonomous defenses previously implicated in anti-Chlamydia trachomatis host defense in mice. Igs4 inclusion integrity was restored by caspase inhibitors, indicating that the IFN-γ-mediated destruction of Igs4 inclusions is dependent upon the function of caspases or related prodeath cysteine proteases. We further demonstrated that the Igs4 mutant is immune restricted in an IFN-γ-dependent manner in a mouse infection model, thereby implicating IFN-γ-mediated inclusion destruction and host cell death as potent in vivo host defense mechanisms to which wild-type C. muridarum is resistant. Overall, our results suggest that C. muridarum evolved resistance mechanisms to counter IFN-γ-elicited programmed cell death and the associated destruction of intravacuolar pathogens. IMPORTANCE Multiple obligatory intracellular bacteria in the genus Chlamydia are important pathogens. In humans, strains of C. trachomatis cause trachoma, chlamydia, and lymphogranuloma venereum. These diseases are all associated with extended courses of infection and reinfection that likely reflect the ability of chlamydiae to evade various aspects of host immune responses. Interferon-stimulated genes, driven in part by the cytokine interferon gamma, restrict the host range of various Chlamydia species, but how these pathogens evade interferon-stimulated genes in their definitive host is poorly understood. Various Chlamydia species can inhibit death of their host cells and may have evolved this strategy to evade prodeath signals elicited by host immune responses. We present evidence that chlamydia-induced programmed cell death resistance evolved to counter interferon- and immune-mediated killing of Chlamydia-infected cells.
format	article
author	Amanda M. Giebel Shuai Hu Krithika Rajaram Ryan Finethy Evelyn Toh Julie A. Brothwell Sandra G. Morrison Robert J. Suchland Barry D. Stein Jörn Coers Richard P. Morrison David E. Nelson
author_facet	Amanda M. Giebel Shuai Hu Krithika Rajaram Ryan Finethy Evelyn Toh Julie A. Brothwell Sandra G. Morrison Robert J. Suchland Barry D. Stein Jörn Coers Richard P. Morrison David E. Nelson
author_sort	Amanda M. Giebel
title	Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture
title_short	Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture
title_full	Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture
title_fullStr	Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture
title_full_unstemmed	Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture
title_sort	genetic screen in <named-content content-type="genus-species">chlamydia muridarum</named-content> reveals role for an interferon-induced host cell death program in antimicrobial inclusion rupture
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/e8a90bbcb71f4e98a83cb61cb313a9e4
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Genetic Screen in <named-content content-type="genus-species">Chlamydia muridarum</named-content> Reveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture

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