Researchers are making strides in the fight against gastroenteritis
A team led by researchers at Baylor College of Medicine is making strides toward the development of effective preventive and therapeutic strategies for gastroenteritis. Human noroviruses are the leading cause of acute gastroenteritis worldwide, a major global health problem for which there are no specific treatments or vaccines.
“We focused our study in the human norovirus pandemic strain GII.4, the one responsible for causing most cases of gastroenteritis around the world,” said first author Dr. B. Vijayalakshmi Ayyar, senior staff scientist of molecular virology and microbiology in the lab of Dr. Mary K. Estes at Baylor.
An unexpected entry mechanism
Ayyar, Estes and their colleagues worked with human intestinal enteroids, a laboratory model of the human gastrointestinal tract that recapitulates its cellular complexity, diversity and physiology. Human enteroids mimic strain-specific host-virus infection patterns, making them an ideal system to dissect human norovirus infection, identify strain-specific growth requirements and develop and test treatments and vaccines.
“We discovered that the binding of human norovirus GII.4 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. We propose that these pathways could be manipulated to interfere with viral entry in human intestinal cells.”
To our knowledge, this is a previously uncharacterized complex entry process into human enteroids that combines several independent pathways.”
“There may be more molecules involved in this entry pathway than what have been reported for other viruses,” said Estes, Distinguished Service Professor and Cullen Foundation Endowed Chair of molecular virology and microbiology at Baylor. Estes also is the corresponding author of the work and co-director of the Gastrointestinal Experimental Model Systems (GEMS) core at the Texas Medical Center Digestive Diseases Center (DDC). “Other viruses use some components of the pathways mentioned in our paper, but this is the first time a virus has been shown to use all of them together. We now are interested in figuring out the role each of these molecules plays in this novel, interesting process, and whether it relates to the pandemic nature of GII.4.”
New clues into the role of the virus during cellular entry
“We know that the structure of the virus is organized into two domains or parts, a shell domain and a protruding domain,” Ayyar said. “Previously, we thought that all the interactions between the virus and cells involved only the protruding domain. In this work, we found that both the protruding and the shell domains are involved in the entry process. This suggests that virus interactions with cells cause changes in the viral structure that facilitate the cell entry. We also are interested in further exploring how these structural changes are induced and their precise role in the viral entry process.”
Would you like to learn more? Read the paper in Nature Communications.
Other contributors to this work include Khalil Ettayebi, Wilhelm Salmen, Umesh C. Karandikar, Frederick H. Neill, Victoria R. Tenge, Sue E. Crawford, Erhard Bieberich, B. V. Venkataram Prasad and Robert L. Atmar. The authors are affiliated with Baylor College of Medicine or the University of Kentucky.
This research was supported by National Institutes of Health grants P01 AI57788, P30DK56338 that supports the Texas Medical Center Digestive Diseases Center and the Texas Children’s Hospital EM core, T32 AI055413, S10 OD028480 that supported purchasing the Zeiss Laser Scanning Microscope LSM 980 with Airyscan 2 and the RobertWelch Foundation Q1279. The authors would like to acknowledge the Advanced Technology Core Laboratories at Baylor College of Medicine, specifically the Integrated Microscopy Core with funding from the NIH (DK56338, CA125123, ES030285) and CPRIT (RP150578, RP170719).