Herpes Simplex Virus Can Infect the Mind by Evading the Immune Response

Herpes Virus Structure

Herpes simplex virus’s VP1-2 protein can deactivate the early immune response.

Herpes simplex virus (HSV1) infections are initiated at mucosal surfaces the place the virus infects epithelial cells. When HSV1 spreads from the peripheral nerves and into the central nervous system, it may well infect the mind and trigger herpes simplex encephalitis, a uncommon illness with excessive mortality if left untreated. Most often, the innate immune system prevents HSV1 mind an infection, however HSV1 is usually in a position to evade the mind’s defenses. A analysis workforce from Aarhus College, College of Oxford, and College of Gothenburg, led by first writer Chiranjeevi Bodda in Søren Paludan’s lab, found a molecular mechanism that helps HSV1 infect the mind, which they current in a examine that can be revealed at this time (Might 8, 2020) within the Journal of Experimental Drugs (JEM).

The stimulator of interferon genes (STING) protein performs an vital position in immunity, and it’s activated by a virus’s DNA throughout viral an infection. STING initiates a cascade of mobile actions that assist combat the invader. These preliminary efforts embrace gene activation and manufacturing of cytokine proteins equivalent to sort I interferon (IFN) that enhance the immune response. “HSV1 has evolved multiple mechanisms to evade the host cells’ induction of type I IFN,” Bodda explains, “but how HSV1 evades the type I IFN response in the brain were not well understood.”

VP1-2 Suppressing Immunity

Herpes simplex virus (HSV1) replication in mind slices was strongly impaired within the absence of its VP1-2 protein’s de-ubiquitination exercise (ΔDUB, backside row), as proven right here by the diminished variety of virus-producing cells (black). This highlights VP1-2’s position in suppressing immunity. Credit score: Bodda et al. 2020

The analysis workforce labored to determine proteins encoded in HSV1’s genome that promoted HSV1’s immune evasion within the mind. They contaminated mouse mind cells grown in tradition with HSV1 mutants that had been lacking key genes, or whose gene exercise was altered, and located HSV1 containing a mutated VP1-2 gene confirmed elevated innate immune responses. Mice confirmed a equally strong immune response in opposition to HSV1 with mutant VP1-2. This indicated that ordinary VP1-2 suppresses immunity.

The important thing distinction between regular VP1-2 and the mutant VP1-2 was the mutant lacked its capacity to take away a post-translational modification, known as ubiquitin, from different proteins inside host cells after it infects them. Ubiquitin is considered one of a number of post-translational modifications recognized to modulate the STING cascade’s immune response. The workforce discovered that VP1-2 was focusing on the STING exercise in mind immune cells, generally known as microglia. The workforce additional confirmed that VP1-2 can instantly take away STING ubiquitination, which prevented STING from being activated for signaling. “Before this study there was no knowledge on viruses altering ubiquitin in the brain’s immune response,” Paludan says.

“Our study shows that HSV1 targets STING ubiquitination in the brain to promote viral infection and potentially progression to herpes simplex encephalitis,” Bodda says. “A drug that inhibits the virus’s ability to remove ubiquitin could allow brain cells to mount an efficient antiviral response against HSV1. This could especially benefit immunocompromised patients with severe HSV1 brain infection, particularly in cases that are resistant to the standard acyclovir treatment.”

Paludan provides that although the examine focuses on herpesviruses, there are parallels to the coronavirus and relevance to the COVID-19 pandemic. “Our results lead us to hope that if we can prevent viruses from blocking STING, then we can prevent the virus from replicating. That could pave the way for new principles for treatment of herpes, influenza and also the coronavirus.”

Rference: “HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection” by Chiranjeevi Bodda, Line Reinert, Stefanie Fruhwürth, Timmy Richardo, Chenglong Solar, Bao-cun Zhang, Maria Kalamvoki, Anja Pohlmann, Trine Mogensen, Petra Bergström, Lotta Agholme, Peter O’Hare, Beate Sodeik, Mads Gyrd-Hansen, Henrik Zetterberg and Soren Paludan, 8 Might 2020, Journal of Experimental Drugs (JEM).
DOI: 10.1084/jem.20191422

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