Cluster of norovirus virions. Credit score: CDC
Human norovirus, a positive-strand RNA virus that’s the main reason behind viral gastroenteritis accounting for an estimated 685 million circumstances and roughly 212,000 deaths globally per 12 months, has no authorised vaccines or antivirals.
Paving the best way for improved drug therapies, researchers at Baylor School of Drugs and the College of Texas, MD Anderson Most cancers Middle report in Science Advances the invention of replication hubs for human norovirus, which might result in designing antiviral medication to forestall, management or deal with these infections.
“When viruses infect cells, they usually create specialized compartments—replication factories—where they form new viruses that infect more cells causing the disease,” stated first creator Dr. Soni Kaundal, postdoctoral affiliate within the Verna and Marrs McLean Division of Biochemistry and Molecular Pharmacology at Baylor within the lab of Dr. B.V. Venkataram Prasad, corresponding creator of the work.
“However, little is known about norovirus’s replication factories.”
Rising proof exhibits that some replication factories usually usually are not separated from their environment by a membrane. As an alternative, they’re biomolecular condensates, constructions resembling a bubble shaped by liquid-liquid section separation. These condensates selectively incorporate proteins and different supplies wanted for viral replication.
Liquid-like condensates as replication factories have been extensively studied in different viruses, together with the rabies and measles viruses. On this research, the researchers investigated whether or not norovirus kinds biomolecular condensates that function replication hubs.
“We knew that these condensates are often initiated by a single viral protein capable of binding genetic material, having a flexible region and forming oligomers, molecules made of small numbers of repeating units,” Kaundal stated.
The crew started their investigation by making use of bioinformatic evaluation to establish norovirus proteins that might current the traits almost definitely resulting in the formation of liquid condensates.
“Working with the human norovirus pandemic strain GII.4, the one responsible for causing most cases of gastroenteritis around the world, we found that the RNA-dependent RNA polymerase has the highest propensity to form biomolecular condensates,” Kaundal stated.
“This protein has a flexible region, can form oligomers, binds RNA, the norovirus’s genetic material, and plays an essential role during viral replication, making copies of the viral RNA. All these characteristics prompted us to experimentally test whether the GII.4 RNA polymerase drives the formation of biomolecular condensates conducive to viral replication.”
“Our experimental studies show that GII.4 RNA polymerase indeed forms highly dynamic liquid-like condensates at physiologically relevant conditions in the lab and that the flexible region of this protein is critical for this process,” stated Prasad, professor of molecular virology and microbiology and Alvin Romansky Chair in Biochemistry at Baylor.
Prasad can be a member of Baylor’s Dan L Duncan Complete Most cancers Middle. “Furthermore, the condensates are highly dynamic structures: several can merge, forming a larger structure, or they can divide into smaller ones; they also move inside the cell, exchanging materials with their surroundings.”
Subsequent, the researchers investigated whether or not these liquid-like condensates are additionally shaped in human norovirus-infected human intestinal cells.
Till not too long ago, learning how norovirus replicates inside cells has been troublesome as a result of researchers lacked an efficient organic system through which to develop the virus within the lab. However in 2016, the lab of Dr. Mary Estes at Baylor and colleagues succeeded at cultivating human norovirus strains in human intestinal enteroid cultures.
Also called mini-guts, these cultures are a laboratory mannequin of the human gastrointestinal tract that recapitulates its mobile complexity, variety and physiology. Human enteroids mimic strain-specific host-virus an infection patterns, making them a really perfect system to dissect human norovirus an infection, as within the present research, to establish strain-specific progress necessities and develop and check therapies and vaccines.
“We showed that liquid-like condensates are formed in human norovirus-infected human intestinal enteroid cultures as well as in the HEK293T human cell line grown in the lab. We propose that these condensates are replication hubs for human norovirus, an elegant solution to the puzzling question of how ribosome-assisted translation of the viral genome is segregated from its replication by the viral polymerase in positive-strand RNA viruses,” Prasad stated.
“Our bioinformatics analysis also showed that the RNA polymerases of almost all the norovirus strains have a high propensity to form these replication factories, suggesting that this may be a common phenomenon of most noroviruses.”
“This is a remarkable paper, and I was glad we could validate the findings in virus-infected cells using our human intestinal enteroids cultivation system for human norovirus,” stated Estes, Distinguished Service Professor and Cullen Basis Endowed Chair of molecular virology and microbiology at Baylor.
Estes is also the co-director of the Gastrointestinal Experimental Mannequin Programs core on the Texas Medical Middle Digestive Ailments Middle and a member of Baylor’s Dan L Duncan Complete Most cancers Middle.
The findings not solely present new perception into human norovirus replication but additionally open new targets for designing antivirals for human norovirus infections, which stay a critical menace in youngsters and immunocompromised sufferers.
Different contributors to this work embody Ramakrishnan Anish, B. Vijayalakshmi Ayyar, Sreejesh Shanker, Gundeep Kaur, Sue E. Crawford, Jeroen Pollet and Fabio Stossi.
Extra info:
Soni Kaundal et al, RNA-dependent RNA polymerase of predominant human norovirus kinds liquid-liquid section condensates as viral replication factories, Science Advances (2024). DOI: 10.1126/sciadv.adp9333. www.science.org/doi/10.1126/sciadv.adp9333
Offered by
Baylor School of Drugs
Quotation:
Discovery of norovirus replication hubs presents new antiviral targets (2024, December 20)
retrieved 20 December 2024
from https://medicalxpress.com/information/2024-12-discovery-norovirus-replication-hubs-antiviral.html
This doc is topic to copyright. Other than any honest dealing for the aim of personal research or analysis, no
half could also be reproduced with out the written permission. The content material is supplied for info functions solely.
