Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>

ABSTRACT Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions bet...

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Autores principales:	Sarah Inglesfield, Aleksandra Jasiulewicz, Matthew Hopwood, James Tyrrell, George Youlden, Maria Mazon-Moya, Owain R. Millington, Serge Mostowy, Sara Jabbari, Kerstin Voelz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	fungal infection fungal pathogenesis host-pathogen interactions innate immunity macrophages mathematical modeling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f1b98d0dbaa14af99af59a25e9187700
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spelling	oai:doaj.org-article:f1b98d0dbaa14af99af59a25e91877002021-11-15T15:53:26ZRobust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>10.1128/mBio.02010-172150-7511https://doaj.org/article/f1b98d0dbaa14af99af59a25e91877002018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02010-17https://doaj.org/toc/2150-7511ABSTRACT Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and real-time in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. IMPORTANCE Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.Sarah InglesfieldAleksandra JasiulewiczMatthew HopwoodJames TyrrellGeorge YouldenMaria Mazon-MoyaOwain R. MillingtonSerge MostowySara JabbariKerstin VoelzAmerican Society for Microbiologyarticlefungal infectionfungal pathogenesishost-pathogen interactionsinnate immunitymacrophagesmathematical modelingMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	fungal infection fungal pathogenesis host-pathogen interactions innate immunity macrophages mathematical modeling Microbiology QR1-502
spellingShingle	fungal infection fungal pathogenesis host-pathogen interactions innate immunity macrophages mathematical modeling Microbiology QR1-502 Sarah Inglesfield Aleksandra Jasiulewicz Matthew Hopwood James Tyrrell George Youlden Maria Mazon-Moya Owain R. Millington Serge Mostowy Sara Jabbari Kerstin Voelz Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>
description	ABSTRACT Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and real-time in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. IMPORTANCE Mucormycosis is a dramatic fungal infection frequently leading to the death of patients. We know little about the immune response to the fungus causing this infection, although evidence points toward defects in early immune events after infection. Here, we dissect this early immune response to infectious fungal spores. We show that specialized white blood cells (phagocytes) rapidly respond to these spores and accumulate around the fungus. However, we demonstrate that the mechanisms that enable phagocytes to kill the fungus fail, allowing for survival of spores. Instead a cluster of phagocytes resembling an early granuloma is formed around spores to control the latent infection. This study is the first detailed analysis of early granuloma formation during a fungal infection highlighting a latent stage that needs to be considered for clinical management of patients.
format	article
author	Sarah Inglesfield Aleksandra Jasiulewicz Matthew Hopwood James Tyrrell George Youlden Maria Mazon-Moya Owain R. Millington Serge Mostowy Sara Jabbari Kerstin Voelz
author_facet	Sarah Inglesfield Aleksandra Jasiulewicz Matthew Hopwood James Tyrrell George Youlden Maria Mazon-Moya Owain R. Millington Serge Mostowy Sara Jabbari Kerstin Voelz
author_sort	Sarah Inglesfield
title	Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>
title_short	Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>
title_full	Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>
title_fullStr	Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>
title_full_unstemmed	Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>
title_sort	robust phagocyte recruitment controls the opportunistic fungal pathogen <italic toggle="yes">mucor circinelloides</italic> in innate granulomas <italic toggle="yes">in vivo</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/f1b98d0dbaa14af99af59a25e9187700
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Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen <italic toggle="yes">Mucor circinelloides</italic> in Innate Granulomas <italic toggle="yes">In Vivo</italic>

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