SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release

Area of Science:

• Gastroenterology
• Virology
• Cell Biology

Background:

• Diarrhea affects 30-50% of COVID-19 patients, but the underlying mechanism is not fully understood.
• This study investigates the role of enterocyte-enteric neuron interactions in SARS-CoV-2-induced diarrhea.
• SARS-CoV-2 infection causes endoplasmic reticulum (ER) stress in enterocytes, leading to the release of damage-associated molecular patterns (DAMPs).

Purpose of the Study:

• To elucidate the mechanism of SARS-CoV-2-induced diarrhea.
• To examine the role of ER stress and DAMPs in enterocyte-enteric neuron signaling.
• To understand how SARS-CoV-2 disrupts gut electrolyte and fluid homeostasis.

Main Methods:

• Primary mouse enteric neurons (EN) were exposed to conditioned media from SARS-CoV-2-infected Caco-2 cells or tunicamycin (ER stress inducer).
• Vasoactive intestinal peptide (VIP) expression and secretion by EN were measured.
• Surface expression of the Na+/H+ exchanger 3 (NHE3) was assessed using surface biotinylation.

Main Results:

• SARS-CoV-2 infection induced ER stress markers (BiP/GRP78) and DAMP release (HSP70) in Caco-2 cells.
• Conditioned media from infected cells increased VIP mRNA expression in EN.
• VIP, in conjunction with ER stress, synergistically reduced NHE3 membrane expression in Caco-2 cells.

Conclusions:

• SARS-CoV-2 infection triggers ER stress in enterocytes, releasing DAMPs that upregulate VIP expression and release from enteric neurons.
• VIP inhibits intestinal fluid absorption by downregulating NHE3 expression in enterocytes.
• These findings highlight epithelial-enteric neuronal crosstalk as a key factor in COVID-19-related diarrhea.