Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease

ABSTRACT Cryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoform...

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Autores principales:	Kiem Vu, Rick Tham, John P. Uhrig, George R. Thompson, Sarisa Na Pombejra, Mantana Jamklang, Jennifer M. Bautos, Angie Gelli
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a2978472faeb4b1181847256404fae40
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spelling	oai:doaj.org-article:a2978472faeb4b1181847256404fae402021-11-15T15:47:38ZInvasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease10.1128/mBio.01101-142150-7511https://doaj.org/article/a2978472faeb4b1181847256404fae402014-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01101-14https://doaj.org/toc/2150-7511ABSTRACT Cryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoformans revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of C. neoformans (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of C. neoformans lacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in an in vitro model of the human blood-brain barrier (BBB). A mammalian host infected with the mpr1Δ null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The in vivo studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1 in Saccharomyces cerevisiae resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1’s specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform. IMPORTANCE Cryptococcus neoformans is a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. For C. neoformans to penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration of C. neoformans across the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis.Kiem VuRick ThamJohn P. UhrigGeorge R. ThompsonSarisa Na PombejraMantana JamklangJennifer M. BautosAngie GelliAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 3 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Kiem Vu Rick Tham John P. Uhrig George R. Thompson Sarisa Na Pombejra Mantana Jamklang Jennifer M. Bautos Angie Gelli Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease
description	ABSTRACT Cryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoformans revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of C. neoformans (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of C. neoformans lacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in an in vitro model of the human blood-brain barrier (BBB). A mammalian host infected with the mpr1Δ null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The in vivo studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1 in Saccharomyces cerevisiae resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1’s specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform. IMPORTANCE Cryptococcus neoformans is a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. For C. neoformans to penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration of C. neoformans across the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis.
format	article
author	Kiem Vu Rick Tham John P. Uhrig George R. Thompson Sarisa Na Pombejra Mantana Jamklang Jennifer M. Bautos Angie Gelli
author_facet	Kiem Vu Rick Tham John P. Uhrig George R. Thompson Sarisa Na Pombejra Mantana Jamklang Jennifer M. Bautos Angie Gelli
author_sort	Kiem Vu
title	Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease
title_short	Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease
title_full	Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease
title_fullStr	Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease
title_full_unstemmed	Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease
title_sort	invasion of the central nervous system by <named-content content-type="genus-species">cryptococcus neoformans</named-content> requires a secreted fungal metalloprotease
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/a2978472faeb4b1181847256404fae40
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Invasion of the Central Nervous System by <named-content content-type="genus-species">Cryptococcus neoformans</named-content> Requires a Secreted Fungal Metalloprotease

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