Alphaherpesvirus infection of mice primes PNS neurons to an inflammatory state regulated by TLR2 and type I IFN signaling.

TitleAlphaherpesvirus infection of mice primes PNS neurons to an inflammatory state regulated by TLR2 and type I IFN signaling.
Publication TypeJournal Article
Year of Publication2019
AuthorsLaval, K, Van Cleemput, J, Vernejoul, JB, Enquist, LW
JournalPLoS Pathog
Volume15
Issue11
Paginatione1008087
Date Published2019 11
ISSN1553-7374
KeywordsAlphaherpesvirinae, Animals, Antiviral Agents, Herpesviridae Infections, Inflammation, Interferon Type I, Male, Mice, Mice, Inbred C57BL, Neurons, Peripheral Nervous System, Toll-Like Receptor 2, Virus Replication
Abstract

<p>Pseudorabies virus (PRV), an alphaherpesvirus closely related to Varicella-Zoster virus (VZV) and Herpes simplex type 1 (HSV1) infects mucosa epithelia and the peripheral nervous system (PNS) of its host. We previously demonstrated that PRV infection induces a specific and lethal inflammatory response, contributing to severe neuropathy in mice. So far, the mechanisms that initiate this neuroinflammation remain unknown. Using a mouse footpad inoculation model, we found that PRV infection rapidly and simultaneously induces high G-CSF and IL-6 levels in several mouse tissues, including the footpad, PNS and central nervous system (CNS) tissues. Interestingly, this global increase occurred before PRV had replicated in dorsal root ganglia (DRGs) neurons and also was independent of systemic inflammation. These high G-CSF and IL-6 levels were not caused by neutrophil infiltration in PRV infected tissues, as we did not detect any neutrophils. Efficient PRV replication and spread in the footpad was sufficient to activate DRGs to produce cytokines. Finally, by using knockout mice, we demonstrated that TLR2 and IFN type I play crucial roles in modulating the early neuroinflammatory response and clinical outcome of PRV infection in mice. Overall, these results give new insights into the initiation of virus-induced neuroinflammation during herpesvirus infections.</p>

DOI10.1371/journal.ppat.1008087
Alternate JournalPLoS Pathog
PubMed ID31675371
PubMed Central IDPMC6824567
Grant ListR01 NS033506 / NS / NINDS NIH HHS / United States
R01 NS060699 / NS / NINDS NIH HHS / United States