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Research reveals new mechanism by which rotavirus induces diarrhea

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Research reveals new mechanism by which rotavirus induces diarrhea

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Rotavirus causes gastroenteritis, a situation that features diarrhea, poor nutrient absorption and weight reduction. Extreme instances lead to roughly 128,000 deaths yearly in infants and youngsters worldwide. Regardless of intense analysis on how rotavirus causes diarrhea, there’s nonetheless no full reply, however on this new examine researchers at Baylor Faculty of Drugs report a brand new mechanism by which rotavirus induces diarrhea, interfering with the traditional absorption of vitamins within the gut.

The examine, revealed in Proceedings of the Nationwide Academy of Sciences, is the primary to indicate that rotavirus-altered lipid metabolism within the gut performs a job within the illness. Rotavirus an infection results in the degradation of DGAT1, an enzyme concerned in regular lipid droplet formation in intestinal cells, which in flip reduces the manufacturing of key nutrient transporters and different proteins required for regular intestinal nutrient absorption, resulting in diarrhea.

We needed to higher perceive how rotavirus exploits mobile processes to copy. We used the well-established monkey kidney cell (MA104) mannequin of rotavirus an infection in addition to human intestinal enteroids (HIEs) for these research. HIEs have revolutionized the examine of gastrointestinal (GI) viruses like rotavirus. These multicellular, non-transformed cell cultures retain host genetic properties, mobile group and recapitulate the perform of the human gastrointestinal epithelium. They function biologically related mannequin programs for finding out human GI infections.”


Dr. Sue E. Crawford, co-corresponding writer, assistant professor of molecular virology and microbiology at Baylor

“We knew that rotavirus triggers the formation of extra lipid droplets than regular within the cells it infects, because it turns the lipid droplets into virus factories. Whereas we have been finding out this course of, we found that rotavirus binds to and breaks down or degrades DGAT1, an enzyme that contributes to the formation of the lipid droplets,” Crawford stated.

Because the researchers regarded deeper into DGAT1, they found that there are kids who’re born with mutations in DGAT1 that render the enzyme nonfunctional. “These kids have extreme continual diarrhea, which typically is deadly,” stated co-first writer, Hunter Smith, graduate scholar in Dr. Mary Estes’ and Crawford’s lab at Baylor. “This led us to suppose that rotavirus-mediated degradation of DGAT1 may very well be a mechanism by which the virus induces diarrhea.”

It was all the time thought that the virus precipitated diarrhea by infecting the intestinal cells that take up vitamins, killing them and consequently disrupting the nutrient absorption mechanisms of the gut. “However we discovered a brand new mechanism by which rotavirus induces diarrhea. Like the kids who’ve a genetic DGAT1 deficiency that causes diarrhea, when rotavirus degrades DGAT1 the result’s lowered manufacturing of the enzymes which are concerned in degrading the meals we eat and disruption of the mechanisms that transport vitamins into cells, which ends up in diarrhea,” Smith stated.

“It was very sudden that rotavirus has a protein that interacts with and degrades DGAT1 and that eliminating DGAT1 would result in all these downstream results that might trigger diarrhea,” Crawford stated.

Mutations on DGAT1 in kids and the hyperlink to diarrhea have been identified within the final 10 years. “Earlier than that no person would have stated that there was any affiliation between issues with this enzyme and diarrhea,” stated Estes, Distinguished Service Professor of Molecular Virology and Microbiology and Cullen Basis Endowed Chair at Baylor. She is also a member of Baylor’s Dan L Duncan Complete Most cancers Heart and co-corresponding writer of this work with Crawford. “It was very shocking {that a} rotavirus protein that till now was solely identified to be necessary for the virus to copy, additionally performs a job in inflicting diarrhea, a significant part of the illness. The truth that it is not a capsid protein or a part of the construction that envelops the genetic materials of the virus, as we often would suppose, tells us that we must always not assume that nonstructural proteins don’t play roles in inflicting illness.”

Co-first writer Zheng Liu, Jeanette M. Criglar, Antonio J. Valentin, Umesh Karandikar and Xi-Lei Zeng additionally contributed to this work. The authors are affiliated with Baylor Faculty of Drugs or Rice College.

This work was supported by Nationwide Institutes of Well being grants (R01 AI080656, U19 AI116497 and 1S10OD028480), funding from P30 Most cancers Heart Assist Grant (NCI-CA125123), P30 Digestive Illness Heart (NIDDK-56338-13/15), CPRIT (RP150578) and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

Rotavirus causes gastroenteritis, a situation that features diarrhea, poor nutrient absorption and weight reduction. Extreme instances lead to roughly 128,000 deaths yearly in infants and youngsters worldwide. Regardless of intense analysis on how rotavirus causes diarrhea, there’s nonetheless no full reply, however on this new examine researchers at Baylor Faculty of Drugs report a brand new mechanism by which rotavirus induces diarrhea, interfering with the traditional absorption of vitamins within the gut.

The examine, revealed in Proceedings of the Nationwide Academy of Sciences, is the primary to indicate that rotavirus-altered lipid metabolism within the gut performs a job within the illness. Rotavirus an infection results in the degradation of DGAT1, an enzyme concerned in regular lipid droplet formation in intestinal cells, which in flip reduces the manufacturing of key nutrient transporters and different proteins required for regular intestinal nutrient absorption, resulting in diarrhea.

“We needed to higher perceive how rotavirus exploits mobile processes to copy,” stated co-corresponding writer Dr. Sue E. Crawford, assistant professor of molecular virology and microbiology at Baylor. “We used the well-established monkey kidney cell (MA104) mannequin of rotavirus an infection in addition to human intestinal enteroids (HIEs) for these research. HIEs have revolutionized the examine of gastrointestinal (GI) viruses like rotavirus. These multicellular, non-transformed cell cultures retain host genetic properties, mobile group and recapitulate the perform of the human gastrointestinal epithelium. They function biologically related mannequin programs for finding out human GI infections.”

“We knew that rotavirus triggers the formation of extra lipid droplets than regular within the cells it infects, because it turns the lipid droplets into virus factories. Whereas we have been finding out this course of, we found that rotavirus binds to and breaks down or degrades DGAT1, an enzyme that contributes to the formation of the lipid droplets,” Crawford stated.

Because the researchers regarded deeper into DGAT1, they found that there are kids who’re born with mutations in DGAT1 that render the enzyme nonfunctional. “These kids have extreme continual diarrhea, which typically is deadly,” stated co-first writer, Hunter Smith, graduate scholar in Dr. Mary Estes’ and Crawford’s lab at Baylor. “This led us to suppose that rotavirus-mediated degradation of DGAT1 may very well be a mechanism by which the virus induces diarrhea.”

It was all the time thought that the virus precipitated diarrhea by infecting the intestinal cells that take up vitamins, killing them and consequently disrupting the nutrient absorption mechanisms of the gut. “However we discovered a brand new mechanism by which rotavirus induces diarrhea. Like the kids who’ve a genetic DGAT1 deficiency that causes diarrhea, when rotavirus degrades DGAT1 the result’s lowered manufacturing of the enzymes which are concerned in degrading the meals we eat and disruption of the mechanisms that transport vitamins into cells, which ends up in diarrhea,” Smith stated.

“It was very sudden that rotavirus has a protein that interacts with and degrades DGAT1 and that eliminating DGAT1 would result in all these downstream results that might trigger diarrhea,” Crawford stated.

Mutations on DGAT1 in kids and the hyperlink to diarrhea have been identified within the final 10 years. “Earlier than that no person would have stated that there was any affiliation between issues with this enzyme and diarrhea,” stated Estes, Distinguished Service Professor of Molecular Virology and Microbiology and Cullen Basis Endowed Chair at Baylor. She is also a member of Baylor’s Dan L Duncan Complete Most cancers Heart and co-corresponding writer of this work with Crawford. “It was very shocking {that a} rotavirus protein that till now was solely identified to be necessary for the virus to copy, additionally performs a job in inflicting diarrhea, a significant part of the illness. The truth that it is not a capsid protein or a part of the construction that envelops the genetic materials of the virus, as we often would suppose, tells us that we must always not assume that nonstructural proteins don’t play roles in inflicting illness.”

Co-first writer Zheng Liu, Jeanette M. Criglar, Antonio J. Valentin, Umesh Karandikar and Xi-Lei Zeng additionally contributed to this work. The authors are affiliated with Baylor Faculty of Drugs or Rice College.

This work was supported by Nationwide Institutes of Well being grants (R01 AI080656, U19 AI116497 and 1S10OD028480), funding from P30 Most cancers Heart Assist Grant (NCI-CA125123), P30 Digestive Illness Heart (NIDDK-56338-13/15), CPRIT (RP150578) and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.

Supply:

Journal reference:

Liu, Z., et al. (2023) Rotavirus-mediated DGAT1 degradation: A pathophysiological mechanism of viral-induced malabsorptive diarrhea. PNAS. doi.org/10.1073/pnas.2302161120.

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