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Source: SARS-CoV-2 Research  Dec 15, 2021  5 months ago
French Study Reveals That SARS-Cov-2 Variants With N501Y Mutation Extend Host Range To Mice And Warns New Variants Could Arise And Infect Humans!
French Study Reveals That SARS-Cov-2 Variants With N501Y Mutation Extend Host Range To Mice And Warns New Variants Could Arise And Infect Humans!
Source: SARS-CoV-2 Research  Dec 15, 2021  5 months ago
SARS-CoV-2 Research: Scientists from Institut Pasteur, Université de Paris-France have in a new study discovered the SARS-CoV-2 variants bearing the N501Y mutation have extended host range to include mice and warns that mice getting infected with the SARS-CoV-2 coronavirus from humans could potentially help create more concerning variants that can then be passed back to humans.

 
Receptor recognition is a major determinant of viral host range, infectivity and pathogenesis. Emergences have been associated with serendipitous events of adaptation upon encounters with novel hosts, and the high mutation rate of RNA viruses may explain their frequent host shifts. SARS-CoV-2 extensive circulation in humans results in the emergence of variants, including variants of concern (VOCs) with diverse mutations notably in the spike, and increased transmissibility or immune escape.

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The study team showed that, unlike the initial and Delta variants, the three VOCs bearing the N501Y mutation can infect common laboratory mice. Contact transmission occurred from infected to naive mice through two passages. This host range expansion likely results from an increased binding of the spike to the mouse ACE2. Together with the observed contact transmission, it raises the possibility of wild rodent secondary reservoirs enabling the emergence of new variants.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.03.18.436013v2
 
The study team first measured the capacity of a panel of low-passage clinical isolates belonging to the initial lineages and to each of the VOCs lineages to infect mouse cells expressing the murine ACE2 receptor (DBT-mACE2), by comparison with VeroE6 cells. Unlike the ancestral viruses (B and B.1 lineages) which did not replicate in these cells, all VOCs carrying the N501Y change replicated to high titers at 48h post infection.
 
The SARS-CoV-2 Research study team next inoculated 8-week-old BALB/c and C57BL/6 mice intranasally (i.n.) with a representative virus of either the most prevalent SARS-CoV-2 lineage in 2020 (basal to B.1, carrying the D614G substitution) or the four VOCs lineages and the team measured the viral load and titer in the lungs on day 3 post infection (dpi3). Consistently with what was reported for the ancestral virus, low amounts of viral RNA and no infectious particles were dete cted with the D614G (B.1) virus. https://www.nature.com/articles/s41586-020-2708-8
 
It was noted that similar observations were made with a Delta variant.
 
In contrast, inoculation with Beta or Gamma variants yielded virus replication to high titers in lung tissues in both mouse strains. A strain of the A.27 lineage, harboring the N501Y change without the D614G mutation, similarly yielded comparably high viral titer in the lungs of C57BL/6 mice.
 
Interestingly, while the Alpha strain resulted in significantly lower viral load than Beta or Gamma, an Alpha variant carrying the E484K mutation in the spike (present in Beta and Gamma) yielded viral titer comparable to the other N501Y isolates.
 
In order to capture the time course of the productive infection with the Beta and Gamma viruses, the study team also sampled infected mice at day 2 and 4, revealing an early peak of infection.
 
 The study findings showed that none of these variants induced clinical signs and only the Beta variant induced a moderate and transient body weight loss at dpi2-3.
 
Three days after Beta or Gamma virus inoculation, histological evaluation of the lung ranged from normal morphology to moderate lesions characterized by multifocal interstitial infiltrates of lymphocytes, plasma cells, macrophages and rare neutrophils (around bronchi/bronchioles and blood vessels) and by degenerating epithelial cells in the bronchial and bronchiolar spaces.
 
Detailed anti-N immunohistochemistry revealed the presence of infected cells in bronchiolar epithelium, bronchiolar and alveolar spaces and alveolar walls.
 
The study findings importantly showed that the Beta variant can disseminate in mice by close contact.
 
The study findings also clearly demonstrated that, once they have been exposed to the virus, mice can transmit the virus to others, which raises major questions on the risk of mice or other rodents living in very large numbers in proximity to humans, of becoming secondary reservoirs for SARS-CoV-2 in regions where the N501Y-carrying variants circulate, from where they could evolve separately and potentially spillback to humans.
 
In fact, rodents have been hypothesized as the ancestral host of some betacoronaviruses (lineage A, which includes the seasonal human coronaviruses OC43 and HKU1.
 https://pubmed.ncbi.nlm.nih.gov/25552712/
https://pubmed.ncbi.nlm.nih.gov/30704076/
 
Similar and actionable concerns were raised upon the detection of SARS-CoV-2 in Mink farms in The Netherlands (Oreshkova et al., 2020) and in Denmark (Lassaunière R et al., 2020) due to the density of animals housed, and the detection of changes in the virus genome.
https://pubmed.ncbi.nlm.nih.gov/32553059/
https://files.ssi.dk/Mink-cluster-5-short-report_AFO2
 
Although rodent densities are highly variable and more difficult to estimate, multiple spillovers have been detected in free-living White-tailed deer populations in North America.
https://www.biorxiv.org/content/10.1101/2021.10.31.466677v1.full
 
The study team posits that host range should be closely monitored along the continued evolution of SARS-CoV-2.
 
The probability of a more dangerous SARS-CoV-2 mutant arising in mice and causing a potential spillback to humans with catastrophic consequences are extremely high and in fact, it has already been predicted that such an event occurring should be witnessed in 2022.
 
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