Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection

ABSTRACT A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a...

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Autores principales:	Marcin Stawowczyk, Shamoon Naseem, Valeria Montoya, Darren P. Baker, James Konopka, Nancy C. Reich
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	ISG chemokines interferons invasive candidiasis reactive oxygen species Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/45378e4cce3b4a958df966f7cef87517
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spelling	oai:doaj.org-article:45378e4cce3b4a958df966f7cef875172021-11-15T15:53:26ZPathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection10.1128/mBio.00365-182150-7511https://doaj.org/article/45378e4cce3b4a958df966f7cef875172018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00365-18https://doaj.org/toc/2150-7511ABSTRACT A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Candida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and C. albicans is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with C. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive C. albicans appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior to C. albicans infection. IFN-β treatment promoted pathology and death from C. albicans infection. We provide evidence that IFIT2 increases the pathological effects of invasive C. albicans and that administration of IFN-β has deleterious effects during infection. IMPORTANCE The attributable mortality associated with systemic C. albicans infections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemic C. albicans infection. This result infers a harmful effect of IFN during C. albicans infection and is supported by our finding that administration of IFN-β prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response to C. albicans, and they suggest that IFN therapies present a risk factor for disseminated candidiasis.Marcin StawowczykShamoon NaseemValeria MontoyaDarren P. BakerJames KonopkaNancy C. ReichAmerican Society for MicrobiologyarticleISGchemokinesinterferonsinvasive candidiasisreactive oxygen speciesMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	ISG chemokines interferons invasive candidiasis reactive oxygen species Microbiology QR1-502
spellingShingle	ISG chemokines interferons invasive candidiasis reactive oxygen species Microbiology QR1-502 Marcin Stawowczyk Shamoon Naseem Valeria Montoya Darren P. Baker James Konopka Nancy C. Reich Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection
description	ABSTRACT A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Candida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and C. albicans is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with C. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive C. albicans appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior to C. albicans infection. IFN-β treatment promoted pathology and death from C. albicans infection. We provide evidence that IFIT2 increases the pathological effects of invasive C. albicans and that administration of IFN-β has deleterious effects during infection. IMPORTANCE The attributable mortality associated with systemic C. albicans infections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemic C. albicans infection. This result infers a harmful effect of IFN during C. albicans infection and is supported by our finding that administration of IFN-β prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response to C. albicans, and they suggest that IFN therapies present a risk factor for disseminated candidiasis.
format	article
author	Marcin Stawowczyk Shamoon Naseem Valeria Montoya Darren P. Baker James Konopka Nancy C. Reich
author_facet	Marcin Stawowczyk Shamoon Naseem Valeria Montoya Darren P. Baker James Konopka Nancy C. Reich
author_sort	Marcin Stawowczyk
title	Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection
title_short	Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection
title_full	Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection
title_fullStr	Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection
title_full_unstemmed	Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection
title_sort	pathogenic effects of ifit2 and interferon-β during fatal systemic <named-content content-type="genus-species">candida albicans</named-content> infection
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/45378e4cce3b4a958df966f7cef87517
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Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic <named-content content-type="genus-species">Candida albicans</named-content> Infection

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