<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway

ABSTRACT Mucormycosis is an emerging fungal infection that is often lethal due to the ineffectiveness of current therapies. Here, we have studied the first stage of this infection—the germination of Mucor circinelloides spores inside phagocytic cells—from an integrated transcriptomic and functional...

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Autores principales:	Carlos Pérez-Arques, María Isabel Navarro-Mendoza, Laura Murcia, Carlos Lax, Pablo Martínez-García, Joseph Heitman, Francisco E. Nicolás, Victoriano Garre
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	emerging pathogens host-pathogen interaction innate immunity mucormycosis transcriptomics Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/16949cbc2b44439c8d9f8cae4741ccfb
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spelling	oai:doaj.org-article:16949cbc2b44439c8d9f8cae4741ccfb2021-11-15T15:55:13Z<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway10.1128/mBio.02765-182150-7511https://doaj.org/article/16949cbc2b44439c8d9f8cae4741ccfb2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02765-18https://doaj.org/toc/2150-7511ABSTRACT Mucormycosis is an emerging fungal infection that is often lethal due to the ineffectiveness of current therapies. Here, we have studied the first stage of this infection—the germination of Mucor circinelloides spores inside phagocytic cells—from an integrated transcriptomic and functional perspective. A relevant fungal gene network is remodeled in response to phagocytosis, being enriched in crucial functions to survive and germinate inside the phagosome, such as nutritional adaptation and response to oxidative stress. Correspondingly, the phagocytic cells induced a specific proinflammatory and apoptotic response to the pathogenic strain. Deletion of fungal genes encoding putative transcription factors (atf1, atf2, and gcn4), extracellular proteins (chi1 and pps1), and an aquaporin (aqp1) revealed that these genes perform important roles in survival following phagocytosis, germination inside the phagosome, and virulence in mice. atf1 and atf2 play a major role in these pathogenic processes, since their mutants showed the strongest phenotypes and both genes control a complex gene network of secondarily regulated genes, including chi1 and aqp1. These new insights into the initial phase of mucormycosis define genetic regulators and molecular processes that could serve as pharmacological targets. IMPORTANCE Mucorales are a group of ancient saprophytic fungi that cause neglected infectious diseases collectively known as mucormycoses. The molecular processes underlying the establishment and progression of this disease are largely unknown. Our work presents a transcriptomic study to unveil the Mucor circinelloides genetic network triggered in fungal spores in response to phagocytosis by macrophages and the transcriptional response of the host cells. Functional characterization of differentially expressed fungal genes revealed three transcription factors and three extracellular proteins essential for the fungus to survive and germinate inside the phagosome and to cause disease in mice. Two of the transcription factors, highly similar to activating transcription factors (ATFs), coordinate a complex secondary gene response involved in pathogenesis. The significance of our research is in characterizing the initial stages that lead to evasion of the host innate immune response and, in consequence, the dissemination of the infection. This genetic study offers possible targets for novel antifungal drugs against these opportunistic human pathogens.Carlos Pérez-ArquesMaría Isabel Navarro-MendozaLaura MurciaCarlos LaxPablo Martínez-GarcíaJoseph HeitmanFrancisco E. NicolásVictoriano GarreAmerican Society for Microbiologyarticleemerging pathogenshost-pathogen interactioninnate immunitymucormycosistranscriptomicsMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	emerging pathogens host-pathogen interaction innate immunity mucormycosis transcriptomics Microbiology QR1-502
spellingShingle	emerging pathogens host-pathogen interaction innate immunity mucormycosis transcriptomics Microbiology QR1-502 Carlos Pérez-Arques María Isabel Navarro-Mendoza Laura Murcia Carlos Lax Pablo Martínez-García Joseph Heitman Francisco E. Nicolás Victoriano Garre <italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
description	ABSTRACT Mucormycosis is an emerging fungal infection that is often lethal due to the ineffectiveness of current therapies. Here, we have studied the first stage of this infection—the germination of Mucor circinelloides spores inside phagocytic cells—from an integrated transcriptomic and functional perspective. A relevant fungal gene network is remodeled in response to phagocytosis, being enriched in crucial functions to survive and germinate inside the phagosome, such as nutritional adaptation and response to oxidative stress. Correspondingly, the phagocytic cells induced a specific proinflammatory and apoptotic response to the pathogenic strain. Deletion of fungal genes encoding putative transcription factors (atf1, atf2, and gcn4), extracellular proteins (chi1 and pps1), and an aquaporin (aqp1) revealed that these genes perform important roles in survival following phagocytosis, germination inside the phagosome, and virulence in mice. atf1 and atf2 play a major role in these pathogenic processes, since their mutants showed the strongest phenotypes and both genes control a complex gene network of secondarily regulated genes, including chi1 and aqp1. These new insights into the initial phase of mucormycosis define genetic regulators and molecular processes that could serve as pharmacological targets. IMPORTANCE Mucorales are a group of ancient saprophytic fungi that cause neglected infectious diseases collectively known as mucormycoses. The molecular processes underlying the establishment and progression of this disease are largely unknown. Our work presents a transcriptomic study to unveil the Mucor circinelloides genetic network triggered in fungal spores in response to phagocytosis by macrophages and the transcriptional response of the host cells. Functional characterization of differentially expressed fungal genes revealed three transcription factors and three extracellular proteins essential for the fungus to survive and germinate inside the phagosome and to cause disease in mice. Two of the transcription factors, highly similar to activating transcription factors (ATFs), coordinate a complex secondary gene response involved in pathogenesis. The significance of our research is in characterizing the initial stages that lead to evasion of the host innate immune response and, in consequence, the dissemination of the infection. This genetic study offers possible targets for novel antifungal drugs against these opportunistic human pathogens.
format	article
author	Carlos Pérez-Arques María Isabel Navarro-Mendoza Laura Murcia Carlos Lax Pablo Martínez-García Joseph Heitman Francisco E. Nicolás Victoriano Garre
author_facet	Carlos Pérez-Arques María Isabel Navarro-Mendoza Laura Murcia Carlos Lax Pablo Martínez-García Joseph Heitman Francisco E. Nicolás Victoriano Garre
author_sort	Carlos Pérez-Arques
title	<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
title_short	<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
title_full	<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
title_fullStr	<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
title_full_unstemmed	<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway
title_sort	<italic toggle="yes">mucor circinelloides</italic> thrives inside the phagosome through an atf-mediated germination pathway
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/16949cbc2b44439c8d9f8cae4741ccfb
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<italic toggle="yes">Mucor circinelloides</italic> Thrives inside the Phagosome through an Atf-Mediated Germination Pathway

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