OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection

Joshua Ames, Tejabhiram Yadavalli, Rahul Suryawanshi, James Hopkins, Alexander Agelidis, Chandrashekhar Patil, Brian Fredericks, Henry Tseng, Tibor Valyi-Nagy and Deepak Shukla ()
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Joshua Ames: University of Illinois at Chicago, College of Medicine
Tejabhiram Yadavalli: University of Illinois at Chicago, College of Medicine
Rahul Suryawanshi: University of Illinois at Chicago, College of Medicine
James Hopkins: University of Illinois at Chicago, College of Medicine
Alexander Agelidis: University of Illinois at Chicago, College of Medicine
Chandrashekhar Patil: University of Illinois at Chicago, College of Medicine
Brian Fredericks: University of Illinois at Chicago, College of Medicine
Henry Tseng: Duke Eye Center and Department of Ophthalmology, Duke University Medical Center
Tibor Valyi-Nagy: University of Illinois at Chicago, College of Medicine
Deepak Shukla: University of Illinois at Chicago, College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Fast-replicating neurotropic herpesviruses exemplified by herpes simplex virus-1 (HSV-1) naturally infect the central nervous system (CNS). However, most individuals intrinsically suppress the virus during a primary infection and preclude it from significantly damaging the CNS. Optineurin (OPTN) is a conserved autophagy receptor with little understanding of its role in neurotropic viral infections. We show that OPTN selectively targets HSV-1 tegument protein, VP16, and the fusion glycoprotein, gB, to degradation by autophagy. OPTN-deficient mice challenged with HSV-1 show significant cognitive decline and susceptibility to lethal CNS infection. OPTN deficiency unveils severe consequences for recruitment of adaptive immunity and suppression of neuronal necroptosis. Ocular HSV-1 infection is lethal without OPTN and is rescued using a necroptosis inhibitor. These results place OPTN at the crux of neuronal survival from potentially lethal CNS viral infections.

Date: 2021
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DOI: 10.1038/s41467-021-25642-z

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