Researchers at Baylor College of Medicine, along with other institutions, have identified differences in how certain human GII.4 norovirus strains infect cells. These viruses are a leading cause of acute viral gastroenteritis worldwide, for which there are currently no vaccines or antiviral treatments.
The study, published in the Proceedings of the National Academy of Sciences, focused on comparing the dominant GII.4 Sydney strain with other GII.4 variants. The findings indicate that these viruses have developed a particularly effective mechanism for entering human gut cells, with notable differences between strains.
“To study the entry mechanism of human norovirus GII.4, we compared the binding and entry of multiple GII.4 variants using GII.4 virus-like particles (VLPs) and human intestinal enteroids,” said Dr. B. Vijayalakshmi Ayyar, senior staff scientist in the Department of Molecular Virology and Microbiology at Baylor.
Virus-like particles (VLPs) were used in this research as non-infectious models that mimic real viruses but do not contain genetic material or cause disease. Human intestinal enteroids provided a laboratory model replicating the complexity and function of the gastrointestinal tract, allowing scientists to observe how different virus strains interact with host cells.
“In a previous study, we discovered that the binding of human norovirus GII.4 VLPs to enteroid cells wounds the cells’ membranes, which in turn triggers a membrane repair mechanism to the injury site, activating another cellular pathway known as the CLIC pathway,” Ayyar said. “We observed crosstalk between CLIC-mediated internalization of viral particles and host repair mechanisms.”
The researchers examined these processes further in their latest work. “We found that after viral particles bind to human enteroids, they form clusters on the cell surface triggering a series of events that result in viral entry and infection,” said Dr. B.V. Venkataram Prasad, professor at Baylor and member of its Dan L Duncan Comprehensive Cancer Center. “Importantly, our study revealed that structure changes in the viral particles are required to assemble the dynamic clusters on the cell surface, driving a multistep entry pathway.”
Not all GII.4 variants behaved identically; only some formed distinct clusters on cell surfaces—a trait linked to increased membrane wounding and higher rates of entry and replication within enteroids.
“When we studied differences between clustering and non-clustering GII.4 strains, we identified two amino acids on the protruding domain of the norovirus particles, named V333 and R339, that were critical mediators of clustering and entry,” Ayyar said. “Mutating or blocking these amino acids disrupted clustering and viral entry.”
“We know there are many differences among different human norovirus strains. Some of them relate to the immunology of the virus and some to how the virus enters the cell,” said Dr. Robert L. Atmar, John S. Dunn clinical research professor at Baylor College of Medicine.“Learning more about what distinguishes individual strains so we can better understand why some viruses predominate more than others is exciting.This study on GII.4 human norovirus is an important step toward that goal.”
“By increasing our understanding of how human norovirus enters susceptible cells, these findings are bringing us closer to identifying and characterizing the elusive host receptor for human norovirus,” said Dr.Mary K.Estes,c orresponding author and Distinguished Service Professor at Baylor.“This work also contributes important insights that advance development of targeted preventive treatments and therapies that we hope one day will contribute to relieve the burden these viruses pose to the human population.”
Contributors included researchers from Baylor College of Medicine,the Food and Drug Administration,and University of Gothenburg(Sweden). Funding was provided by various NIH grants,the Robert Welch Foundation,U.S.Food & Drug Administration intramural funds,a grant agreement between Swedish Government & Västra Götaland Region,and Hillevax Inc.
