Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry

ABSTRACT Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies...

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Autores principales:	Hamid Salimi, Matthew D. Cain, Xiaoping Jiang, Robyn A. Roth, Wandy L. Beatty, Chengqun Sun, William B. Klimstra, Jianghui Hou, Robyn S. Klein
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	IFNAR Venezuelan encephalitis virus western equine encephalitis virus alphavirus blood-brain barrier caveola-mediated transcytosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3b44feea351f4155ab631a8dee939ddc
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spelling	oai:doaj.org-article:3b44feea351f4155ab631a8dee939ddc2021-11-15T15:56:57ZEncephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry10.1128/mBio.02731-192150-7511https://doaj.org/article/3b44feea351f4155ab631a8dee939ddc2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02731-19https://doaj.org/toc/2150-7511ABSTRACT Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative strains also demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit (NVU), differentially rendering brain endothelial cells, pericytes, and astrocytes permissive to viral replication. Transmission and immunoelectron microscopy revealed early events in virus internalization and Cav-1 association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS and that IFN differentially restricts this process at the BBB. IMPORTANCE VEEV, WEEV, and eastern equine encephalitis virus (EEEV) are emerging infectious diseases in the Americas, and they have caused several major outbreaks in the human and horse population during the past few decades. Shortly after infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. Neuroinvasion has been associated with virus entry into the CNS directly from the bloodstream; however, the underlying molecular mechanisms have remained largely unknown. Here, we demonstrate that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPases within brain endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower viral burdens in the brain than in similarly infected wild-type animals. These studies identify a potentially targetable pathway to limit neuroinvasion by alphaviruses.Hamid SalimiMatthew D. CainXiaoping JiangRobyn A. RothWandy L. BeattyChengqun SunWilliam B. KlimstraJianghui HouRobyn S. KleinAmerican Society for MicrobiologyarticleIFNARVenezuelan encephalitis viruswestern equine encephalitis virusalphavirusblood-brain barriercaveola-mediated transcytosisMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	IFNAR Venezuelan encephalitis virus western equine encephalitis virus alphavirus blood-brain barrier caveola-mediated transcytosis Microbiology QR1-502
spellingShingle	IFNAR Venezuelan encephalitis virus western equine encephalitis virus alphavirus blood-brain barrier caveola-mediated transcytosis Microbiology QR1-502 Hamid Salimi Matthew D. Cain Xiaoping Jiang Robyn A. Roth Wandy L. Beatty Chengqun Sun William B. Klimstra Jianghui Hou Robyn S. Klein Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry
description	ABSTRACT Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative strains also demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit (NVU), differentially rendering brain endothelial cells, pericytes, and astrocytes permissive to viral replication. Transmission and immunoelectron microscopy revealed early events in virus internalization and Cav-1 association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS and that IFN differentially restricts this process at the BBB. IMPORTANCE VEEV, WEEV, and eastern equine encephalitis virus (EEEV) are emerging infectious diseases in the Americas, and they have caused several major outbreaks in the human and horse population during the past few decades. Shortly after infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. Neuroinvasion has been associated with virus entry into the CNS directly from the bloodstream; however, the underlying molecular mechanisms have remained largely unknown. Here, we demonstrate that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPases within brain endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower viral burdens in the brain than in similarly infected wild-type animals. These studies identify a potentially targetable pathway to limit neuroinvasion by alphaviruses.
format	article
author	Hamid Salimi Matthew D. Cain Xiaoping Jiang Robyn A. Roth Wandy L. Beatty Chengqun Sun William B. Klimstra Jianghui Hou Robyn S. Klein
author_facet	Hamid Salimi Matthew D. Cain Xiaoping Jiang Robyn A. Roth Wandy L. Beatty Chengqun Sun William B. Klimstra Jianghui Hou Robyn S. Klein
author_sort	Hamid Salimi
title	Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry
title_short	Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry
title_full	Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry
title_fullStr	Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry
title_full_unstemmed	Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry
title_sort	encephalitic alphaviruses exploit caveola-mediated transcytosis at the blood-brain barrier for central nervous system entry
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/3b44feea351f4155ab631a8dee939ddc
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Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry

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