The Interplay Between Optineurin and Other Host Factors During HSV-1 Infection.

Herpes simplex type 1 (HSV-1) is endemic worldwide, with 80% of the population latently infected. HSV-1 is known to undermine host defense responses and invade the nervous system to establish latency in peripheral ganglia. Stress factors can reactivate this virus and recurrent herpes episodes have been associated with different neurodegenerative disorders. Understanding the key host factors that can be targeted to protect host from HSV-1 spread can pave way for future therapeutics. Our lab has previously found that Optineurin (OPTN) can restrict HSV-1 by utilizing autophagy to selectively degrade key HSV-1 proteins. Reports have implied phosphorylation of OPTN by TBK1 as a requisite for activation of OPTN mediated autophagy. We provide new insight about TBK1 independent HSV-1 restriction by OPTN. We also unveil a novel OPTN-MLKL axis governing not only the viral replication process but also safeguarding against subsequent neurodegeneration. We show that MLKL can aid HSV-1 infection by facilitating its transport to the nucleus. Increase in MLKL expression during infection can also lead to activation of death modalities leading to death of oligodendrocytes and subsequent demyelination. Optineurin can negatively modulate MLKL expression and inhibit HSV-1 induced etiologies. These findings combined will generate new understanding of the host mechanisms that drive infection and pave a path towards developing therapeutic intervention to combat HSV-1 induced pathologies.