Skip to main content

Enhanced #RNA #replication and #pathogenesis in recent #SARS-CoV-2 #variants harboring the L260F mutation in NSP6

Abstract

The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape. Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across the entire viral genome and their functional impact is not well understood. To address the contribution of these mutations, we reconstructed genomes of recent Omicron variants with disabled Spike expression (replicons) to systematically compare their RNA replication capabilities independently from Spike. We also used a single reference replicon and complemented it with various Omicron variant Spike proteins to quantify viral entry capabilities in single-round infection assays. Viral entry and RNA replication were negatively correlated, suggesting that as variants evolve reduced entry functions under growing immune pressure on Spike, RNA replication increases as a compensatory mechanism. We identified multiple mutations across the viral genome that enhanced viral RNA replication. NSP6 emerged as a hotspot with a distinct L260F mutation independently arising in the BQ.1.1 and XBB.1.16 variants. Using mutant and revertant NSP6 viral clones, the L260F mutation was validated to enhance viral replication in cells and increase pathogenesis in mice. Notably, this mutation enhanced host lipid droplet consumption by NSP6 without impacting its known ER-zippering function or double-membrane vesicle morphology. Collectively, a systematic analysis of RNA replication of recent Omicron variants defined NSP6 key role in viral RNA replication that provides insight into evolutionary trajectories of recent variants with possible therapeutic implications.

Source: BioRxIV, https://www.biorxiv.org/content/10.1101/2024.12.30.628795v1?rss=1

_____

Comments

Popular posts from this blog

#USA, Two more #human cases of #H5N1 #birdflu reported in #California

Two cases of bird flu have been reported in San Joaquin County, California, local health officials said. According to a press release issued Friday and reported by the Sacramento Bee , health officials with San Joaquin County Public Health Services said both cases were farm workers who were exposed to infected animals . Both people are showing mild symptoms and are recovering, officials said, adding that there are 34 total confirmed cases across California. In a warning posted on Facebook, health officials said bird flu was “spreading in several farms such as poultry and cattle” and urged residents to take precautions to prevent the spread of the disease. Precautions include the use of protective equipment when handling poultry, dairy cattle or other animals that may be infected, and when handling raw and unpasteurized milk. (...) There are currently 60 confirmed cases of bird flu in the country . While most of the cases are in California , other states with confirmed cases include Col...

#PuertoRico - High pathogenicity avian #influenza #H5N1 viruses (#poultry) (Inf. with) - Immediate notification

Highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b was confirmed on one poultry premises in Culebra Municipality, Puerto Rico . This is the first confirmed case of HPAI in poultry from Puerto Rico. Full genotyping confirms the virus as a reassortant of the A3 genotype with North American wild bird lineage viruses ( AM PB2, PA, NP ). Comparisons of the virus to other recent detections from wild birds and North America reports are in progress. The USDA Animal and Plant Health Inspection Service (APHIS), in conjunction with State Animal Health and Wildlife Officials, are conducting comprehensive epidemiological investigations and enhanced surveillance in response to the HPAI H5N1 related events. Source: WOAH,  https://wahis.woah.org/#/in-review/6185 _____