Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis

Chhatbar, Chintan; Detje, Claudia N.; Grabski, Elena; Borst, Katharina; Spanier, Julia; Ghita, Luca; Elliott, David A.; Jordão, Marta Joana Costa; Mueller, Nora; Sutton, James; Prajeeth, Chittappen Kandiyil; Gudi, Viktoria; Klein, Michael A.; Prinz, Marco; Bradke, Frank; Stangel, Martin; Kalinke, Ulrich

doi:10.1016/j.celrep.2018.09.003

Cited by 85 publications

(114 citation statements)

References 55 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…Type I IFN induction is not limited to viral infection and can be caused by other immune stimuli; however, sustained IFN expression is observed only during antiviral signaling (Amit et al, 2009). Both neurons and glia express IFNs and their receptors (Chhatbar et al, 2018). Interestingly, we found that one of the two IFN receptor subunits, IFNAR1, is highly expressed specifically in ventral horn neurons of the spinal cord and that it is depleted from the spinal cord of ALS-FUS patients ( Figure S7).…”

Section: Discussionmentioning

confidence: 84%

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Shelkovnikova

Skelt

et al. 2019

Cell Reports

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 84%

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Shelkovnikova

Skelt

et al. 2019

Cell Reports

View full text Add to dashboard Cite

show abstract

“…Given that viremia arises as early as 8 h after VEEV infection, BMECs are likely among the first cell types exposed to virions. Such exposure may trigger innate immune responses (e.g., type I IFNs), which can influence intercellular communication at the NVU (38). Indeed, in the context of IFNAR deficiency, VEEV and WEEV replicate within BMECs and astrocytes, respectively.…”

Section: Discussionmentioning

confidence: 99%

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

Salehiniya

Cain

Jiang

et al. 2020

mBio

View full text Add to dashboard Cite

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.

show abstract

“…Such exposure may trigger innate immune responses (e.g. type I IFNs), which can influence intercellular communication at the NVU (35). Indeed, in the context of IFNAR deficiency, VEEV and WEEV replicate within BMECs and astrocytes, respectively.…”

Section: Discussionmentioning

confidence: 99%

Encephalitic alphaviruses exploit caveolae-mediated transcytosis at the blood-brain barrier for CNS entry

Salehiniya¹,

Cain²,

Jiang³

et al. 2019

Preprint

View full text Add to dashboard Cite

21Venezuelan and Western equine encephalitis viruses (VEEV and WEEV) invade the CNS early during 22 infection, via neuronal and hematogenous routes (1, 2). While viral replication mediates host-shut off, 23 including expression of type I interferons (IFN) (3, 4), few studies have addressed how alphaviruses 24 gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-25 brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the 26 CNS occurs via caveolin (Cav)-1-mediated transcytosis (Cav-MT) across an intact BBB, which is 27 impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and non-replicative strains also 28 demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit 29 (NVU), differentially rendering brain endothelial cells, pericytes and astrocytes permissive to viral 30 replication. Transmission and immunoelectron microscopy revealed early events in virus internalization 31and Cav-1-association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS 32 VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained 33 unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS, and that IFN 34 differentially restricts this process at the BBB. 35 36 3 Importance 37 VEEV, WEEV and EEEV are emerging infectious diseases in the Americas, and they have caused 38 several major outbreaks in the human and horse population during the past few decades. Shortly after 39 infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. 40Neuroinvasion has been associated with virus entry into the CNS directly from the blood-stream, 41 however the underlying molecular mechanisms have remained largely unknown. Here we demonstrate 42 that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and 43 utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPAses within brain 44 endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower 45 viral burdens than in similarly infected wild-type animals. These studies identify a potentially targetable 46 pathway to limit neuroinvasion by alphaviruses. 47 50

show abstract

Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis

Cited by 85 publications

References 55 publications

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

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

Encephalitic alphaviruses exploit caveolae-mediated transcytosis at the blood-brain barrier for CNS entry

Contact Info

Product

Resources

About