Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice

Linköpings universitet, Avdelningen för molekylär medicin och virologi Linköpings universitet, Medicinska fakulteten Linköpings universitet, Avdelningen för kirurgi, ortopedi och onkologi Linköpings universitet, Avdelningen för inflammation och infektion Karolinska Inst, Sweden AMER SOC MICROBIOLOGY 2020

Increased intestinal permeability has been proposed as a mechanism of rotavirus-induced diarrhea. Studies with humans and mice have, however, shown that rotavirus leaves intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections. Gastrointestinal permeability is regulated by the vagus nerve and the enteric nervous system, which is composed of neurons and enteric glial cells (EGCs). We investigated whether the vagus nerve, serotonin (5-HT), EGCs, and neurotropic factors contribute to maintaining gut barrier homeostasis during rotavirus infection. Using subdiaphragmatic vagotomized and 5-HT3 receptor knockout mice, we found that the unaffected epithelial barrier during rotavirus infection is independent of the vagus nerve but dependent on 5-HT signaling through enteric intrinsic 5-HT3 receptors. Immunofluorescence analysis showed that rotavirus-infected enterocytes were in close contact with EGCs and enteric neurons and that the glial cell-derived neurotrophic factor (GDNF) was strongly upregulated in enterocytes of infected mice. Moreover, rotavirus and 5-HT activated EGCs (P < 0.001). Using Ussing chambers, we found that GDNF and S-nitrosoglutathione (GSNO) led to denser epithelial barriers in small intestinal resections from noninfected mice (P < 0.01) and humans (P < 0.001) and that permeability was unaffected in rotavirus-infected mice. GSNO made the epithelial barrier denser in Caco-2 cells by increasing the expression of the tight junction protein zona occludens 1 (P < 0.001), resulting in reduced passage of fluorescein isothiocyanate dextran (P < 0.05) in rotavirus-infected monolayers. This is the first report to show that neurotropic factors contribute to maintaining the gut epithelial barrier during viral insult. IMPORTANCE Human and mouse studies have shown that rotavirus infection is associated with low inflammation and unaffected intestinal barrier at the time of diarrhea
Funding Agencies|Swedish Research CouncilSwedish Research Council [2014-02827, 201802862]; Mucosa Infection and Inflammation Center (MIIC)

diarrhea; neurotrophic factors; permeability; rotavirus; Immunology; Immunologi; Article in journal; info:eu-repo/semantics/article; text

10.1128.mBio.02834-19

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info:eu-repo/semantics/openAccess

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UPE oai:DiVA.org:liu-165107
0000-0002-9770-4623
0000-0002-5349-2569
0000-0002-6820-0215
doi:10.1128/mBio.02834-19
PMID 31964731
ISI:000518763400044
1234598130

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