Language

English

Publication Date

1-17-2025

Journal

Science Advances

DOI

10.1126/sciadv.adq8115

PMID

39823322

PMCID

PMC11740935

PubMedCentral® Posted Date

1-17-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Viruses engage in a variety of processes to subvert host defenses and create an environment amenable to replication. Here, using rotavirus as a prototype, we show that calcium conductance out of the endoplasmic reticulum by the virus encoded ion channel, NSP4, induces intercellular calcium waves that extend beyond the infected cell and contribute to pathogenesis. Viruses that lack the ability to induce this signaling show diminished viral shedding and attenuated disease in a mouse model of rotavirus diarrhea. This implicates nonstructural protein 4 (NSP4) as a virulence factor and provides mechanistic insight into its mode of action. Critically, this signaling induces a transcriptional signature characteristic of interferon-independent innate immune activation, which is not observed in response to a mutant NSP4 that does not conduct calcium. This implicates calcium dysregulation as a means of pathogen recognition, a theme broadly applicable to calcium-altering pathogens beyond rotavirus.

Keywords

Animals, Viral Nonstructural Proteins, Rotavirus, Mice, Calcium Signaling, Rotavirus Infections, Toxins, Biological, Humans, Calcium, Glycoproteins, Endoplasmic Reticulum, Host-Pathogen Interactions, Disease Models, Animal, Immunity, Innate

Published Open-Access

yes

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