Overview of the Trending Enteric Viruses and Their Pathogenesis in Intestinal Epithelial Cell Infection

Abstract

Enteric virus infection is a major public health issue worldwide. Enteric viruses have become epidemic infectious diseases in several countries. Enteric viruses primarily infect the gastrointestinal tract and complete their life cycle in intestinal epithelial cells. These viruses are transmitted via the fecal-oral route through contaminated food, water, or person to person and cause similar common symptoms, including vomiting, abdominal pain, and diarrhea. Diarrheal disease is the third leading cause of death in children under five years of age, accounting for approximately 1.7 billion cases and 443,832 deaths annually in this age group. Additionally, some enteric viruses can invade other tissues, leading to severe conditions and even death. The pathogenic mechanisms of enteric viruses are also unclear. In this review, we organized the research on trending enteric virus infections, including rotavirus, norovirus, adenovirus, Enterovirus-A71, Coxsackievirus A6, and Echovirus 11. Furthermore, we discuss the gastrointestinal effects and pathogenic mechanisms of SARS-CoV-2 in intestinal epithelial cells, given the gastrointestinal symptoms observed during the COVID-19 pandemic. We conducted a literature review on their pathogenic mechanisms, which serves as a guide for formulating future treatment strategies for enteric virus infections.

Keywords: enteric virus; intestinal epithelial cells; viral pathogenesis.

Figure 1

The mechanism of RV pathogenesis. RV produces NSP4 while infecting IECs. This protein promotes the transportation of Ca²⁺ from the ER to the cytoplasm, which causes Ca²⁺-dependent diarrhea. NSP4 can be secreted extracellularly, where it stimulates the expression of PLC in uninfected cells, increasing the production of IP3. This causes further release of Ca²⁺ from the ER into the cytoplasm. The resulting increase in cytoplasmic Ca²⁺ concentration disrupts tight junction integrity, leading to water influx into the intestinal lumen. Additionally, elevated cytoplasmic Ca²⁺ induces the secretion of 5-HT, which stimulates the myenteric plexus, enhancing intestinal motility. The stimulated myenteric plexus further activates the submucosal plexus to release VIP, increasing cAMP production in IECs. This leads to the secretion of NaCl and water into the intestinal lumen, ultimately causing diarrhea. RV, rotavirus; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; 5-HT, 5-hydroxytryptamine; and VIP, vasoactive intestinal peptide.

Figure 2

The potential route of EV-A71 invades the central neuron system. EV-A71 primarily infects and replicates in IECs. The generated EV-A71 exits from host cells by lytic and non-lytic processes and then invades the CNS via several potential pathways: (1) Retrograde axon transport: EV-A71 infects muscle cells and then enters spinal motor nerves, traveling retrogradely along axons to the CNS. (2) Crossing the BBB: EV-A71 circulates in the bloodstream and directly crosses the BBB to invade the CNS. (3) Trojan horse invasion: EV-A71 infects immune cells, which serve as carriers to transport the virus across the BBB into the CNS. (4) Utilize exosome transport: EV-A71 may be packaged within exosomes, which facilitate its crossing of the BBB and subsequent infection of neural cells. blood–brain barrier; EV-A71, Enterovirus A71; IECs, intestinal epithelial cells.