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 6th 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.

Microglia Reduce Herpes Simplex Virus 1 Lethality of Mice with Decreased T Cell and Interferon Responses in Brains

“…A recent study showed that persistent HSV-1 infection of neurons triggers (CD3 + IFNγ + CD8 + ) CD8 T cell response and gastrointestinal neuromuscular dysfunction in the enteric nervous system of mice after orogastric inoculation [45]. This study further found that infiltrating CD8 T cells leads to intestinal dysmotility during HSV-1 infection, as depletion of intestinal CD3 + CD8 + cells by the anti-CD8 monoclonal antibody ameliorates intestinal dysfunction.…”

The mechanisms of nerve injury caused by viral infection in the occurrence of gastrointestinal motility disorder-related diseases

“…Many studies show that they also express mRNAs encoding ORFs 4, 21, 29, 40, 62, and 63, with ORF 62 and 29 proteins in the cytoplasm [ 28 ]. During latent infection, latent genome replication is not completely turned off, and there are several viral genes that accumulate in neurons in addition to latent-associated transcripts [ 29 ]. In contrast, in lytic infection, neurons die within 48 hours when exposed to nonneuronal cell-associated VZV.…”

“…Varicella-zoster virus is a type of neurotropic virus [ 30 ]. Some experiments in which the skin and guts of animals are double-labeled with retrograde tracers have shown that the virus can be transported retrogradely along nerve fibers [ 26 , 29 ]. Sensory nerves innervating the skin become demyelinated within the epidermis.…”

“…HSV-1 has been confirmed to form latent infection after oral inoculation into the lumen of mice [ 29 , 34 – 36 ]. A study has shown that the intestinal epithelium contains immune-related cells, such as M cells, that absorb and transport viral antigens.…”

“…When the virus is latent in neurons, there are no obvious symptoms in the digestive tract. However, when the body is re-infected, the latent infection can be reactivated [ 26 ] and lead to symptomatic or asymptomatic infection of the gastrointestinal tract through various mechanisms or reactions [ 11 , 29 , 50 ] (Fig. 4 ).…”