Credit: CC0 Public domain rotavirus can cause gastroenteritis, a condition that includes diarrhea, nutrient inabsorption, and weight loss. Worldwide, about 128,000 infants and children die each year from severe cases. Although there has been an in-depth study of how rotavirus causes diarrhea, there is still no complete answer, but in this new study, researchers at Baylor College of Medicine report a novel mechanism by which rotavirus induces diarrhea, interfering with the normal absorption of nutrients in the gut.
The study, published in the Proceedings of the National Academy of Sciences, showed for the first time that rotavirus-altered intestinal lipid metabolism plays a role in the disease. Rotavirus infection leads to the degradation of DGAT1, an enzyme involved in the formation <>of normal lipid droplets in intestinal cells, which in turn reduces the production of key nutrient transporters and other proteins required for normal intestinal nutrient absorption, leading to diarrhea.
We want to better understand how rotaviruses use cellular processes to replicate," co-corresponding author Sue E., assistant professor of molecular virology and microbiology at Baylor UniversityDr. Crawford said.
We performed these studies using a well-established monkey kidney cell (MA104) model of rotavirus infection, as well as human enteroid protein (HIE). HIE has revolutionized the study of gastrointestinal (GI) viruses such as rotavirus. These multicellular, non-transforming cell cultures preserve host genetics, cellular organization, and recapitulate the function of the human gastrointestinal epithelium. They can serve as a biologically relevant model system for studying gastrointestinal infections in humans.
We know that rotavirus triggers the formation of more lipid droplets in the cells it infects than normal because it turns lipid droplets into virus factories. When we studied this process, we found that rotavirus binds to DGAT1 and breaks down or degrades <> D<>GAT, an enzyme that helps in lipid droplet formation," Crawford said.
As the researchers delved deeper into DGAT1, they found that some children were born with a mutation in DGAT1 that rendered the enzyme non-functional. "These children have severe, sometimes fatal, chronic diarrhea," said co-first author Hunter Smith, a graduate student in the lab of Dr. Baylor Mary Estes and Crawford. "This leads us to think that rotavirus-mediated degradation of DGAT1 may be a mechanism of virus-induced diarrhea.
It has long been thought that viruses cause diarrhea by infecting the intestinal cells that absorb nutrients, killing them, thereby disrupting the gut's nutrient absorption mechanisms.
But we have discovered a new mechanism by which rotavirus induces diarrhea. Just like children with the hereditary DGAT1 deficiency that causes diarrhea, when rotavirus degrades DGAT1, the result is a reduced production of enzymes involved in degrading the food we eat and disrupting the mechanisms that transport nutrients into the cells, resulting in diarrhea," Smith said.
Very unexpectedly, rotavirus has a protein that interacts with and degrades DGAT1, and eliminating DGAT1 will lead to all of these downstream effects that lead to diarrhea," Crawford said.
Mutations in DGAT10 in children and the link to diarrhea have been known in the last 1 year. "Until then, no one would have said there was any association between the problem with this enzyme and diarrhea," said Estes, Baylor Distinguished Service Professor of Molecular Virology and Microbiology and Cullen Endowment Chair. She is also a member of the Bayledan Duncan Comprehensive Cancer Center and co-authored the work with Crawford.
It is very surprising that so far rotavirus proteins have only been known to be important for viral replication, but also play a role in causing diarrhea, which is a major component of the disease. The fact that it is not part of the capsid protein or the structure that encapsulates the genetic material of the virus, as we usually believe, tells us that we should not assume that non-structural proteins have no role in causing disease.
Co-first authors: Zheng Liu, Jeanette M criglar，antonio j.Valentin, Umesh Karandikar, and Xi Zeng also contributed to this work. The authors are affiliated with Baylor College of Medicine or Rice University.
More information:Zheng Liu et al, Rotavirus-mediated dGAT1 degradation: pathophysiological mechanisms of virus-induced malabsorption diarrhea, Proceedings of the National Academy of Sciences of the United States of America (2023). doi： 10.1073/pnas.2302161120.doi.org/10.1073/pnas.2302161120