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

Author:

Salimi Hamid1,Cain Matthew D.1,Jiang Xiaoping1,Roth Robyn A.1,Beatty Wandy L.1,Sun Chengqun2,Klimstra William B.2,Hou Jianghui1,Klein Robyn S.134

Affiliation:

1. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

2. Department of Immunology and Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

3. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

4. Department of Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA

Abstract

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.

Funder

DTRA

NIH/NINDS

HHS | NIH | National Institute of Allergy and Infectious Diseases

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

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