<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses

ABSTRACT Cryptococcus neoformans infections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal c...

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Autores principales:	Camaron R. Hole, Woei C. Lam, Rajendra Upadhya, Jennifer K. Lodge
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	chitin chitin synthase chitosan inflammation neutrophils Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b8b69574390d42e7869ca5cc72624bfa
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spelling	oai:doaj.org-article:b8b69574390d42e7869ca5cc72624bfa2021-11-15T15:56:57Z<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses10.1128/mBio.03373-192150-7511https://doaj.org/article/b8b69574390d42e7869ca5cc72624bfa2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03373-19https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus neoformans infections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal cell wall is unusual among human-pathogenic fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan-deficient strains of C. neoformans were found to be avirulent and rapidly cleared from the murine lung. Moreover, infection with a chitosan-deficient C. neoformans strain lacking three chitin deacetylases (cda1Δcda2Δcda3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild-type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase-mediated formation of chitosan. Mice inoculated with the chs3Δ strain at a dose previously shown to induce protection with the cda1Δcda2Δcda3Δ strain die within 36 h after installation of the organism. Mortality was not dependent on viable fungi, as mice inoculated with a heat-killed preparation of the chs3Δ strain died at the same rate as mice inoculated with a live chs3Δ strain, suggesting that the rapid onset of death was host mediated, likely caused by an overexuberant immune response. Histology, cytokine profiling, and flow cytometry indicate a massive neutrophil influx in the mice inoculated with the chs3Δ strain. Mice depleted of neutrophils survived chs3Δ inoculation, indicating that death was neutrophil mediated. Altogether, these studies lead us to conclude that Chs3, along with chitosan, plays critical roles in dampening cryptococcus-induced host inflammatory responses. IMPORTANCE Cryptococcus neoformans is the most common disseminated fungal pathogen in AIDS patients, resulting in ∼200,000 deaths each year. There is a pressing need for new treatments for this infection, as current antifungal therapy is hampered by toxicity and/or the inability of the host’s immune system to aid in resolution of the disease. An ideal target for new therapies is the fungal cell wall. The cryptococcal cell wall is different from the cell walls of many other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan are less pathogenic and strains that are deficient in chitosan are avirulent and can induce protective responses. In this study, we investigated the host responses to a chs3Δ strain, a chitosan-deficient strain, and found that mice inoculated with the chs3Δ strain all died within 36 h and that death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response to Cryptococcus.Camaron R. HoleWoei C. LamRajendra UpadhyaJennifer K. LodgeAmerican Society for Microbiologyarticlechitinchitin synthasechitosaninflammationneutrophilsMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	chitin chitin synthase chitosan inflammation neutrophils Microbiology QR1-502
spellingShingle	chitin chitin synthase chitosan inflammation neutrophils Microbiology QR1-502 Camaron R. Hole Woei C. Lam Rajendra Upadhya Jennifer K. Lodge <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses
description	ABSTRACT Cryptococcus neoformans infections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal cell wall is unusual among human-pathogenic fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan-deficient strains of C. neoformans were found to be avirulent and rapidly cleared from the murine lung. Moreover, infection with a chitosan-deficient C. neoformans strain lacking three chitin deacetylases (cda1Δcda2Δcda3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild-type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase-mediated formation of chitosan. Mice inoculated with the chs3Δ strain at a dose previously shown to induce protection with the cda1Δcda2Δcda3Δ strain die within 36 h after installation of the organism. Mortality was not dependent on viable fungi, as mice inoculated with a heat-killed preparation of the chs3Δ strain died at the same rate as mice inoculated with a live chs3Δ strain, suggesting that the rapid onset of death was host mediated, likely caused by an overexuberant immune response. Histology, cytokine profiling, and flow cytometry indicate a massive neutrophil influx in the mice inoculated with the chs3Δ strain. Mice depleted of neutrophils survived chs3Δ inoculation, indicating that death was neutrophil mediated. Altogether, these studies lead us to conclude that Chs3, along with chitosan, plays critical roles in dampening cryptococcus-induced host inflammatory responses. IMPORTANCE Cryptococcus neoformans is the most common disseminated fungal pathogen in AIDS patients, resulting in ∼200,000 deaths each year. There is a pressing need for new treatments for this infection, as current antifungal therapy is hampered by toxicity and/or the inability of the host’s immune system to aid in resolution of the disease. An ideal target for new therapies is the fungal cell wall. The cryptococcal cell wall is different from the cell walls of many other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan are less pathogenic and strains that are deficient in chitosan are avirulent and can induce protective responses. In this study, we investigated the host responses to a chs3Δ strain, a chitosan-deficient strain, and found that mice inoculated with the chs3Δ strain all died within 36 h and that death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response to Cryptococcus.
format	article
author	Camaron R. Hole Woei C. Lam Rajendra Upadhya Jennifer K. Lodge
author_facet	Camaron R. Hole Woei C. Lam Rajendra Upadhya Jennifer K. Lodge
author_sort	Camaron R. Hole
title	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses
title_short	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses
title_full	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses
title_fullStr	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses
title_full_unstemmed	<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses
title_sort	<named-content content-type="genus-species">cryptococcus neoformans</named-content> chitin synthase 3 plays a critical role in dampening host inflammatory responses
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/b8b69574390d42e7869ca5cc72624bfa
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<named-content content-type="genus-species">Cryptococcus neoformans</named-content> Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses

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