Enteric Ganglioneuritis, a Common Feature in a Subcutaneous TBEV Murine Infection Model

Abstract

Tick-borne encephalitis (TBE) is a severe neurologic disease in Europe and Asia. Disease expression ranges from asymptomatic to severe neurological clinical pictures, involving meningitis, encephalitis, meningoencephalitis and potentially fatal outcome. Humans mostly become infected with TBE virus (TBEV) by the bite of an infected tick. Gastrointestinal (GI) symptoms in humans are mainly attributed to the first viremic phase of TBEV infection with unspecific symptoms and/or resulting from severe neurological impairment of the central nervous system (CNS). We used the subcutaneous TBEV-infection of C57BL/6 mice as a model to analyze GI complications of TBE. We observed the acute distension and segmental dilation of the intestinal tract in 10 of 22 subcutaneously infected mice. Histological analysis revealed an intramural enteric ganglioneuritis in the myenteric and submucosal plexus of the small and large intestine. The numbers of infiltrating macrophages and CD3+ T lymphocytes correlated with the severity of ganglioneuritis, indicating an immune-mediated pathogenesis due to TBEV-infection of the enteric plexus. Our study demonstrates that the inflammation of enteric intramural ganglia presents to be a common feature in TBEV-infected mice. Accordingly, the results of this mouse model emphasize that GI disease manifestation and consequences for long-term sequelae should not be neglected for TBEV-infections in humans and require further investigation.

Induction of humoral and cell-mediated immunity to the NS1 protein of TBEV with recombinant Influenza virus and MVA affords partial protection against lethal TBEV infection in mice

“…Upon dissection at 8 dpi, 100% of the mock-vaccinated and 67% of the vector control mice displayed macroscopically visible acute distension and segmental dilation of the gastrointestinal tract as described previously (54). In contrast, only 50% of mice vaccinated with two doses of IAV-NS1 or MVA-NS1 displayed such lesions.…”

“…Of interest, also in mice that received MVA-NS1/IAV-NS1 or IAV-NS1/MVA-NS1 viral copy numbers, especially in the colon, were reduced >1000-fold compared to mock and vector controlvaccinated mice (Figures 6E, F). Histopathological examination of the intestine revealed histopathological lesions characterized by ganglioneuritis of the myenteric and submucosal plexus in mock and vector controlvaccinated mice 8 dpi as described previously (54). Ganglioneuritis of the myenteric and submucosal plexus are representatively shown in the colon (Figure 8).…”

A recombinant Modified Vaccinia virus Ankara expressing prME of tick-borne encephalitis virus affords mice full protection against TBEV infection

“…Next, we tested the protective efficacy of the respective vaccine preparations against a lethal challenge infection with the homologous TBEV strain Neudoerfl and determined the clinical outcome of infection as well as virus replication in the periphery, CNS, and GIT and associated histopathological changes. In line with previous studies, all control animals displayed body weight loss starting at 7-8 dpi and succumbed to infection between 10 and 14 dpi (66,67). After 8 dpi, TBEV already replicated to high copy numbers in the periphery, CNS, and GIT.…”

“…Moreover, morphological changes of the GIT including cellular necrosis and hypercellularity/inflammatory cell infiltration were observed in the submucosal plexus and, to a lesser extent, in the myenteric plexus of an unprotected control mouse. Enteric ganglioneuritis of the submucosal and myenteric plexus after TBEV infection was reported in mice previously (67). In contrast, all mice vaccinated with MVA-prME were 100% protected without the development of TBE-associated clinical signs.…”

Cross-reactive antibodies against Langat virus protect mice from lethal tick-borne encephalitis virus infection

“…Another previously described key feature of this TBEV infection model is gastrointestinal pathology in majority of affected mice (40). This is most likely a consequence of ganglioneuritis in the plexus myentericus and submucosus leading to dysfunctionality of the gastrointestinal tract.…”