PMID- 35975996 OWN - NLM STAT- MEDLINE DCOM- 20220916 LR - 20230218 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 96 IP - 17 DP - 2022 Sep 14 TI - Herpes Simplex Virus Type 1 Preferentially Enhances Neuro-Inflammation and Senescence in Brainstem of Female Mice. PG - e0108122 LID - 10.1128/jvi.01081-22 [doi] LID - e01081-22 AB - Following acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. The latency associated transcript (LAT) is the only viral gene abundantly expressed during latency. Wild-type (WT) HSV-1 reactivates more efficiently than LAT mutants because LAT promotes establishment and maintenance of latency. While sensory neurons in trigeminal ganglia (TG) are important sites for latency, brainstem is also a site for latency and reactivation from latency. The principal sensory nucleus of the spinal trigeminal tract (Pr5) likely harbors latent HSV-1 because it receives afferent inputs from TG. The locus coeruleus (LC), an adjacent brainstem region, sends axonal projections to cortical structures and is indirectly linked to Pr5. Senescent cells accumulate in the nervous system during aging and accelerate neurodegenerative processes. Generally senescent cells undergo irreversible cell cycle arrest and produce inflammatory cytokines and chemokines. Based on these observations, we hypothesized HSV-1 influences senescence and inflammation in Pr5 and LC of latently infected mice. This hypothesis was tested using a mouse model of infection. Strikingly, female but not age-matched male mice latently infected with a LAT null mutant (dLAT2903) exhibited significantly higher levels of senescence markers and inflammation in LC, including cell cycle inhibitor p16, NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), IL-1alpha, and IL-beta. Conversely, Pr5 in female but not male mice latently infected with WT HSV-1 or dLAT2903 exhibited enhanced expression of important inflammatory markers. The predilection of HSV-1 to induce senescence and inflammation in key brainstem regions of female mice infers that enhanced neurodegeneration occurs. IMPORTANCE HSV-1 (herpes simplex virus 1), an important human pathogen, establishes lifelong latency in neurons in trigeminal ganglia and the central nervous system. In contrast to productive infection, the only viral transcript abundantly expressed in latently infected neurons is the latency associated transcript (LAT). The brainstem, including principal sensory nucleus of the spinal trigeminal tract (Pr5) and locus coeruleus (LC), may expedite HSV-1 spread from trigeminal ganglia to the brain. Enhanced senescence and expression of key inflammatory markers were detected in LC of female mice latently infected with a LAT null mutant (dLAT2903) relative to age-matched male or female mice latently infected with wild-type HSV-1. Conversely, wild-type HSV-1 and dLAT2903 induced higher levels of senescence and inflammatory markers in Pr5 of latently infected female mice. In summary, enhanced inflammation and senescence in LC and Pr5 of female mice latently infected with HSV-1 are predicted to accelerate neurodegeneration. FAU - Sivasubramanian, Mahesh Kumar AU - Sivasubramanian MK AD - Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State Universitygrid.65519.3e, Stillwater, Oklahoma, USA. FAU - Monteiro, Raisa AU - Monteiro R AD - Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State Universitygrid.65519.3e, Stillwater, Oklahoma, USA. FAU - Harrison, Kelly S AU - Harrison KS AD - Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State Universitygrid.65519.3e, Stillwater, Oklahoma, USA. FAU - Plakkot, Bhuvana AU - Plakkot B AD - Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State Universitygrid.65519.3e, Stillwater, Oklahoma, USA. FAU - Subramanian, Madhan AU - Subramanian M AD - Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State Universitygrid.65519.3e, Stillwater, Oklahoma, USA. FAU - Jones, Clinton AU - Jones C AUID- ORCID: 0000-0002-6656-4971 AD - Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State Universitygrid.65519.3e, Stillwater, Oklahoma, USA. LA - eng GR - R01 NS111167/NS/NINDS NIH HHS/United States GR - P20 GM103648/GM/NIGMS NIH HHS/United States GR - R15 HL148844/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220817 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 SB - IM MH - Animals MH - Brain Stem/virology MH - Cellular Senescence MH - Female MH - *Herpes Simplex/pathology MH - *Herpesvirus 1, Human/pathogenicity/physiology MH - Inflammation MH - Male MH - Mice MH - Mice, Inbred NOD MH - *Neuroinflammatory Diseases/virology MH - Trigeminal Ganglion/virology MH - Virus Latency PMC - PMC9472638 OTO - NOTNLM OT - HSV-1 OT - LAT OT - brainstem OT - immune senescence OT - inflammation OT - latency COIS- The authors declare no conflict of interest. EDAT- 2022/08/18 06:00 MHDA- 2022/09/17 06:00 PMCR- 2023/02/17 CRDT- 2022/08/17 09:02 PHST- 2022/08/18 06:00 [pubmed] PHST- 2022/09/17 06:00 [medline] PHST- 2022/08/17 09:02 [entrez] PHST- 2023/02/17 00:00 [pmc-release] AID - 01081-22 [pii] AID - jvi.01081-22 [pii] AID - 10.1128/jvi.01081-22 [doi] PST - ppublish SO - J Virol. 2022 Sep 14;96(17):e0108122. doi: 10.1128/jvi.01081-22. Epub 2022 Aug 17.