Virus World

Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1.

We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context. Here the authors develop a neonatal mouse model for SARS-CoV-2 transmission, characterize differences in viral replication and shedding of variants of concerns, and show that deletion of ORF8 shifts viral replication to the lower respiratory tract and delays transmission.

Published in Nature Comm. (May 25, 2023):

https://doi.org/10.1038/s41467-023-38783-0 

A SARS-CoV-2 mutation that appeared in East Asia early in the pandemic is linked to symptoms milder than those caused by the unmutated version of the virus. In early 2020, researchers in Singapore identified a cluster of COVID-19 cases caused by a SARS-CoV-2 variant missing a chunk of DNA that spanned two genes, ORF7b and ORF8. To determine the consequences of this change, called a deletion, Lisa Ng at the Singapore Immunology Network and colleagues compared people infected with viruses carrying the deletion with those infected by normal viruses (B. E. Young et al. Lancet http://doi.org/d6x7; 2020).

None of the 29 people whose viruses had the mutation needed supplemental oxygen, but 26 of the 92 people whose viruses lacked the mutation did. Viruses carrying the deletion haven’t been detected since March — possibly owing to infection-control measures. The virus responsible for the 2002–04 outbreak of severe acute respiratory syndrome (SARS) acquired a similar deletion in the ORF8 gene, suggesting that this might be an important adaption to infecting humans, the authors say.

Study published in The Lancet (August 18, 2020):

https://doi.org/10.1016/S0140-6736(20)31757-8

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and caused the devastating global pandemic of coronavirus disease 2019 (COVID-19), in part because of its ability to effectively suppress host cell responses1–3. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins4–8, particularly those containing post-translational modifications required for transcriptional regulation9–11. Recent work has demonstrated that SARS-CoV-2 markedly disrupts host cell epigenetic regulation12–14. However, how SARS-CoV-2 controls the host cell epigenome and whether it uses histone mimicry to do so remain unclear. Here we show that the SARS-CoV-2 protein encoded by ORF8 (ORF8) functions as a histone mimic of the ARKS motifs in histone H3 to disrupt host cell epigenetic regulation.

ORF8 is associated with chromatin, disrupts regulation of critical histone post-translational modifications and promotes chromatin compaction. Deletion of either the ORF8 gene or the histone mimic site attenuates the ability of SARS-CoV-2 to disrupt host cell chromatin, affects the transcriptional response to infection and attenuates viral genome copy number. These findings demonstrate a new function of ORF8 and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Further, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19. The SARS-CoV-2 protein ORF8 functions as a mimic of histone H3 to disrupt host cell epigenetic regulation.

Published in Nature (Oct. 5, 2022): 

https://doi.org/10.1038/s41586-022-05282-z