Summary
Researchers have enhanced our understanding of how rotavirus, a leading cause of acute gastroenteritis in children, induces illness. The study reveals that the rotavirus protein NSP4 is critical for disrupting calcium signaling both within infected and neighboring uninfected cells. These disruptions influence the severity of rotavirus infections. The findings, published in Science Advances, suggest NSP4 as a potential target for new treatment and prevention strategies against rotavirus.
Full Story
Rotavirus is the leading cause of severe pediatric acute gastroenteritis worldwide, contributing to nearly 500,000 child deaths annually. Symptoms include watery diarrhea, vomiting, fever, and abdominal pain. Despite the success of oral rehydration therapy and live-attenuated rotavirus vaccines, there is still a need for improved treatments.
Researchers at Baylor College of Medicine, led by Dr. Joseph Hyser, associate professor of molecular virology and microbiology, have investigated how NSP4, a rotavirus protein, influences infection and disease severity. The study shows that NSP4 disrupts calcium signaling, generating "intercellular calcium waves" that affect both infected and uninfected cells. This disruption correlates with increased disease severity.
“We discovered that NSP4 alone is sufficient to generate calcium waves, even without rotavirus infection, and these waves contribute to rotavirus virulence,” said Dr. Hyser.
Key Findings
NSP4’s Role in Calcium Waves:
NSP4 is responsible for inducing aberrant calcium signaling.
Attenuated rotavirus strains with milder NSP4 activity generate fewer calcium waves and cause less severe disease.
Experimental Evidence:
Using human, porcine, and genetically modified rotavirus strains, researchers demonstrated that NSP4 alone triggers calcium waves.
Replacing virulent NSP4 with attenuated versions reduced diarrhea severity in animal models.
Immune Response Implications:
Calcium waves also activate immune responses, linking calcium dysregulation to both disease severity and host defense mechanisms.
Potential Applications
The study highlights NSP4 as a promising target for future therapies aimed at mitigating rotavirus infections. The results may also extend to other viruses with proteins similar to NSP4 that disrupt calcium signaling.
Contributors and Funding
The research was conducted by scientists from Baylor College of Medicine, Indiana University, and Stanford University School of Medicine. Key contributors include J. Thomas Gebert, Francesca J. Scribano, Kristen A. Engevik, Ethan M. Huleatt, Michael R. Eledge, and others.
The study was supported by grants from the National Institutes of Health (NICH R01AI158683, R01DK115507, NIH S10OD028480, among others) and the McNair Foundation M.D./Ph.D. Scholars Program.
Future Directions
This groundbreaking research opens pathways to explore NSP4’s potential as a therapeutic target and to investigate similar mechanisms in other viral infections. Improved understanding of calcium signaling disruptions could lead to innovative strategies to combat rotavirus and related diseases.
Reference
J. Thomas Gebert, Francesca J. Scribano, Kristen A. Engevik, Ethan M. Huleatt, Michael R. Eledge, Lauren E. Dorn, Asha A. Philip, Takahiro Kawagishi, Harry B. Greenberg, John T. Patton, Joseph M. Hyser. Viroporin activity is necessary for intercellular calcium signals that contribute to viral pathogenesis. Science Advances, 2025; 11 (3) DOI: 10.1126/sciadv.adq8115
