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Persistent Herpes Simplex Virus Type 1 Infection of Enteric Neurons Triggers CD8⁺ T Cell Response and Gastrointestinal Neuromuscular Dysfunction.

ABSTRACT: Behind the central nervous system, neurotropic viruses can reach and persist even in the enteric nervous system (ENS), the neuronal network embedded in the gut wall. We recently reported that immediately following orogastric (OG) administration, Herpes simplex virus (HSV)-1 infects murine enteric neurons and recruits mononuclear cells in the myenteric plexus. In the current work, we took those findings a step forward by investigating the persistence of HSV-1 in the ENS and the local adaptive immune responses against HSV-1 that might contribute to neuronal damage in an animal model. Our study demonstrated specific viral RNA transcripts and proteins in the longitudinal muscle layer containing the myenteric plexus (LMMP) up to 10 weeks post HSV-1 infection. CD3⁺CD8⁺INFγ⁺ lymphocytes skewed towards HSV-1 antigens infiltrated the myenteric ganglia starting from the 6^th week of infection and persist up to 10 weeks post-OG HSV-1 inoculation. CD3⁺CD8⁺ cells isolated from the LMMP of the infected mice recognized HSV-1 antigens expressed by infected enteric neurons. In vivo, infiltrating activated lymphocytes were involved in controlling viral replication and intestinal neuromuscular dysfunction. Indeed, by depleting the CD8⁺ cells by administering specific monoclonal antibody we observed a partial amelioration of intestinal dysmotility in HSV-1 infected mice but increased expression of viral genes. Our findings demonstrate that HSV-1 persistently infects enteric neurons that in turn express viral antigens, leading them to recruit activated CD3⁺CD8⁺ lymphocytes. The T-cell responses toward HSV-1 antigens persistently expressed in enteric neurons can alter the integrity of the ENS predisposing to neuromuscular dysfunction.

SUBMITTER: Brun P

PROVIDER: S-EPMC8169984 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Herpes simplex virus 1 (HSV-1) causes a lifelong infection of neurons that innervate barrier sites like the skin and mucosal surfaces like the eye. After primary infection of the cornea, the virus enters latency within the trigeminal ganglion (TG), from which it can reactivate throughout the life of the host. Viral latency is maintained, in part, by virus-specific CD8+ T cells that nonlethally interact with infected neurons. When CD8+ T cell responses are inhibited, HSV-1 can reactivate, and these recurrent reactivation events can lead to blinding scarring of the cornea. In the C57BL/6 mouse, CD8+ T cells specific for the immunodominant epitope from glycoprotein B maintain functionality throughout latency, while CD8+ T cells specific for subdominant epitopes undergo functional impairment that is associated with the expression of the inhibitory checkpoint molecule programmed death 1 (PD-1). Here, we investigate the checkpoint molecule T cell immunoglobulin and mucin domain-containing 3 (Tim-3), which has traditionally been associated with CD8+ T cell exhaustion. Unexpectedly, we found that Tim-3 was preferentially expressed on highly functional ganglionic CD8+ T cells during acute and latent HSV-1 infection. This, paired with data that show that Tim-3 expression on CD8+ T cells in the latently infected TG is influenced by viral gene expression, suggests that Tim-3 is an indicator of recent T cell stimulation, rather than functional compromise, in this model. We conclude that Tim-3 expression is not sufficient to define functional compromise during latency; however, it may be useful in identifying activated cells within the TG during HSV-1 infection.IMPORTANCE Without an effective means of eliminating HSV-1 from latently infected neurons, efforts to control the virus have centered on preventing viral reactivation from latency. Virus-specific CD8+ T cells within the infected TG have been shown to play a crucial role in inhibiting viral reactivation, and with a portion of these cells exhibiting functional impairment, checkpoint molecule immunotherapies have presented a potential solution to enhancing the antiviral response of these cells. In pursuing this potential treatment strategy, we found that Tim-3 (often associated with CD8+ T cell functional exhaustion) is not upregulated on impaired cells but instead is upregulated on highly functional cells that have recently received antigenic stimulation. These findings support a role for Tim-3 as a marker of activation rather than exhaustion in this model, and we provide additional evidence for the hypothesis that there is persistent viral gene expression in the HSV-1 latently infected TG.

Project description:Expression of viral genes and activation of innate antiviral responses during infection result in an increase in reactive oxygen species (ROS) and toxic by-products of energy metabolism which can lead to cell death. The mitochondrion and its associated proteins are crucial regulators of these responses and related pathways such as autophagy and apoptosis. Through a mass spectrometry approach, we have shown that the herpes simplex virus 1 (HSV-1) neurovirulence- and autophagy-modulating protein ICP34.5 interacts with numerous mitochondrion-associated factors. Specifically, we showed that amino acids 68 to 87 of ICP34.5, the domain that binds beclin1 and controls neurovirulence, are necessary for interactions with PGAM5, KEAP1, and other regulators of the antioxidant response, mitochondrial trafficking, and programmed cell death. We further show that while this domain interacts with multiple cellular stress response factors, it does not alter apoptosis or antioxidant gene expression. That said, the attenuated replication of a recombinant virus lacking residues 68 to 87 (termed Δ68-87) in primary human fibroblasts was restored by addition of ferric nitrate. Furthermore, in primary mouse neurons, the perinuclear localization of mitochondria that follows infection with HSV-1 was notably absent following Δ68-87 infection. Through this 20-amino-acid domain, ICP34.5 significantly reduces mitochondrial motility in axons of neurons. We propose the hypothesis that ICP34.5 promotes perinuclear mitochondrial localization by modulating transport of mitochondria through interaction with PGAM5. These data expand upon previous observations of altered mitochondrial dynamics following alphaherpesvirus infections and identify a key determinant of this activity during HSV-1 infections.IMPORTANCE Herpes simplex virus persists lifelong in neurons and can reactivate to cause recurrent lesions in mucosal tissues. A key determinant of virulence is the viral protein ICP34.5, of which residues 68 to 87 significantly contribute to neurovirulence through an unknown mechanism. Our report provides evidence that residues 68 to 87 of ICP34.5 are required for binding mitochondrion-associated factors. These interactions alter mitochondrial dynamics in neurons, thereby facilitating viral replication and pathogenesis.

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Persistent Herpes Simplex Virus Type 1 Infection of Enteric Neurons Triggers CD8⁺ T Cell Response and Gastrointestinal Neuromuscular Dysfunction.

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Dataset Information

Persistent Herpes Simplex Virus Type 1 Infection of Enteric Neurons Triggers CD8+ T Cell Response and Gastrointestinal Neuromuscular Dysfunction.

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OmicsDI is part of the ELIXIR infrastructure

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Persistent Herpes Simplex Virus Type 1 Infection of Enteric Neurons Triggers CD8⁺ T Cell Response and Gastrointestinal Neuromuscular Dysfunction.