Researchers from Baylor College of Medicine and other institutions have advanced the understanding of rotavirus, a leading cause of acute gastroenteritis in children. A study published in Science Advances reveals that the rotavirus protein NSP4 plays a crucial role in infection by disrupting calcium signaling both within infected cells and neighboring uninfected cells. This disruption affects disease severity, offering insights into how NSP4 influences rotavirus virulence. The research suggests that targeting NSP4 could lead to new methods for preventing or treating rotavirus infections.
"Rotavirus alone accounts for one-quarter of all cases of severe pediatric acute gastroenteritis, which typically presents with watery diarrhea, vomiting, fever and abdominal pain. Currently, nearly 500,000 children worldwide die from this condition every year," stated Dr. Joseph Hyser, associate professor at Baylor College of Medicine. "Although oral rehydration therapy and live-attenuated rotavirus vaccines have helped reduce the burden of rotavirus acute gastroenteritis in children worldwide, there is still room for improvement."
The study delves into how NSP4's functions during infection contribute to disease severity. Previously, researchers found that rotavirus triggers abnormal calcium signals called 'intercellular calcium waves' that spread from infected to uninfected cells; inhibiting these signals reduced disease severity.
"The results indicated that it was likely that calcium waves contributed to rotavirus replication and virulence; however, it was not clear how the virus triggered this signal," Hyser explained. "We already had evidence that placed NSP4 at the top of the list of viral proteins that could be involved in triggering calcium waves."
Using human and porcine strains along with novel genetic recombinant strains developed through reverse genetics systems, the team investigated NSP4's role in inducing calcium waves and its link to disease severity using various experimental models.
The findings showed that NSP4 is responsible for generating calcium waves; expressing NSP4 alone in cells produced waves similar to those seen during infection. Notably, attenuated strains with milder effects induced fewer waves than virulent strains. Inserting attenuated NSP4 into a virulent strain reduced wave production and decreased its ability to cause diarrhea in animal models.
"We found that the ability of rotavirus to generate calcium waves goes hand in hand with NSP4; expression of NSP4 alone is sufficient to generate calcium waves, and multiple aspects of rotavirus disease severity correlated with the ability to generate calcium waves," Hyser noted.
Additionally, these calcium waves also triggered an immune response, suggesting a role for calcium dysregulation in viral recognition.
"Altogether, the evidence suggested that NSP4 seemed to be involved in inducing calcium waves linked to both rotavirus disease severity and host cell responses to this aberrant level of calcium signaling," Hyser said.
The implications may extend beyond rotavirus as other viruses with similar proteins might also disrupt calcium signaling.
Contributors include J. Thomas Gebert, Francesca J. Scribano, Kristen A. Engevik among others from Baylor College of Medicine, Indiana University and Stanford University School of Medicine. The study received support from National Institutes of Health grants and the McNair Foundation M.D./Ph.D. Scholars Program.
