Language
English
Publication Date
5-7-2024
Journal
bioRxiv
DOI
10.1101/2024.05.07.592953
PMID
38765995
PMCID
PMC11100750
PubMedCentral® Posted Date
5-7-2024
PubMedCentral® Full Text Version
Pre-Print
Abstract
Rotavirus causes life-threatening diarrhea in children, resulting in ∼200,000 deaths/year. The current treatment during infection is Oral Rehydration Solution which successfully replenishes fluids but does not alleviate diarrhea volume or severity. As a result, there is an urgent need to better understand rotavirus pathophysiology and develop more effective pediatric therapeutics. Rotavirus primarily infects the tips of small intestinal villi, yet has far-reaching effects on cell types distant from infected cells. We recently identified that rotavirus infected cells release the purinergic signaling molecule ADP, which activates P2Y1 receptors on nearby uninfected cells in vitro . To elucidate the role of purinergic signaling via P2Y1 receptors during rotavirus infection in vivo , we used the mouse-like rotavirus strain D6/2 which generates a severe infection in mice. C57BL/6J mouse pups were given an oral gavage of D6/2 rotavirus and assessed over the course of 5-7 days. Beginning at day 1 post infection, infected pups were treated daily by oral gavage with saline or 4 mg/kg MRS2500, a selective P2Y1 antagonist. Mice were monitored for diarrhea severity, diarrhea incidence, and viral shedding. Neonatal mice were euthanized at days 3 and 5 post-infection and small intestine was collected to observe infection. MRS2500 treatment decreased the severity, prevalence, and incidence of rotavirus diarrhea. Viral stool shedding, assessed by qPCR for rotavirus gene levels, revealed that MRS2500 treated pups had significantly lower viral shedding starting at day 4 post infection compared to saline treated pups, which suggests P2Y1 signaling may enhance rotavirus replication. Finally, we found that inhibition of P2Y1 with MRS2500 limited transmitted rotavirus diarrhea to uninfected pups within a litter. Together, these results suggest that P2Y1 signaling is involved in the pathogenesis of a homologous murine rotavirus strain, making P2Y1 receptors a promising anti-diarrheal, anti-viral therapeutic target to reduce rotavirus disease burden.
Published Open-Access
yes
Recommended Citation
Engevik, Kristen A; Scribano, Francesca J; Gebert, J Thomas; et al., "Purinergic Signaling Drives Multiple Aspects of Rotavirus Pathophysiology" (2024). Faculty, Staff and Students Publications. 8097.
https://digitalcommons.library.tmc.edu/baylor_docs/8097