The reduced pathogenicity of rSARS-CoV-2 Nsp1 mutants highlights the potential for targeting Nsp1 for rational design of viral inhibitors and development of live-attenuated vaccine strategies as effective prophylactic and therapeutic treatments to combat SARS-CoV-2 and possibly other CoV infections.
The infant mouse model is used to define the role of the accessory protein ORF8 in SARS-CoV-2 spread and reveal how a SARS-CoV-2 accessory protein can exploit mucosal antiviral responses to increase host contagiousness.
G. Ciabattoni, Stacey Bartlett, M. McGrath et al.· bioRxiv· 0 citations
Various antiviral drug therapies have been developed for the treatment of coronaviruses, particularly SARS-CoV-2. However, the emergence of drug-resistant mutations is detrimental to clinical efficacy and global public health. Antiviral usage exerts selective pressures on viruses that manufacture an environment for resistant strains to emerge, in some cases at a fitness cost. However, the appearance of a compensatory mutation can restore or improve viral fitness, allowing the strain to persist and spread in a population. Here we evaluate the drug resistance mechanisms of multiple SARS-CoV-2 non-structural proteins, including the main protease (Mpro) and the RNA-dependent RNA polymerase (RdRP), which drive polyprotein processing and viral RNA replication, as well as PLPro, EndoU, and Mac1, which contribute to viral replication and counter host innate immune responses. We also discuss several methods that could be used to avoid drug resistance in the future. By integrating the understanding of molecular mechanisms of antiviral treatment with surveillance of resistance-associated mutations and new drug therapies, appropriate clinical approaches can be developed to reduce the impact of drug resistance.
A genome engineering technology is used to change a single amino acid in the viruses’ main protease enzyme to match that of circulating Omicron isolates to demonstrate antiviral efficacy of approved drugs and uncover mutants with reduced drug sensitivity.
The SARS-CoV-2 nucleocapsid (N) protein is one of the most highly expressed proteins during infection and plays crucial roles in the protection and packaging of viral RNA, replication, suppression of the immune response and virus assembly. The N gene and the overlapping accessory open reading frame ORF9b have continually evolved throughout the circulation of the virus, likely due to ongoing adaptation to the human host. This genetic variability influences the interplay of the N protein and its interactors. Yet, little is known about how specific mutations within the N/ORF9b locus of Variants of Concern (VOCs) shape the progression and outcome of infection. Here, we use a multi-omics approach to decipher how these genetic alterations reprogram the host cell by creating Wuhan-Hu-1-based recombinant viruses carrying an isogenic backbone with respective N mutations from the VOCs (called rNs) and comparing their effects at the transcriptome and proteome levels. We found that the mutations induce distinct transcriptional and translational alterations: rN-Alpha drives a stealth-like infection characterized by sustained translation efficiency and specific evasion of the 2’-5’-oligoadenylate synthetase (OAS) innate immune sensor, whereas rN-Delta and rN-BA.2 trigger a highly elevated inflammatory response. For rN-Delta, hyperphosphorylation of the N-protein drives cellular stress culminating in necroptotic cell death. Because these viruses differ only within the N/ORF9b locus, N sequence variation emerges as a determinant of infection outcome in its own right, warranting increased surveillance attention.
J. Berger, Jonas Schröder, Timothy K. Soh et al.· bioRxiv· 0 citations
SARS-CoV-2 evolution enhanced viral fitness and immune evasion, extending the COVID-19 pandemic and resulting in millions of excess deaths. Viral diversity is generated within infected individuals, yet the timing and interplay of viral and immunological forces that drive transmissible evolution are incompletely understood. We developed a multi-scale within host phylodynamic (WiPhy) model of SARS-CoV-2 infection which couples viral replication, innate and acquired immune responses, and viral mutation. We then validated the model against quantitative viral and phylodynamic metrics. Model output predicts that typical acute infections rapidly generate genetic diversity due to accumulation of minor variants which in most cases do not achieve sufficient concentrations for transmission. Delayed innate immune responses correlate with higher peak viral load and diversification, allowing higher transmission risk of the founder virus or with a novel variant that is equally or less fit. In contrast, the risk of transmitting a fitter variant is highest during the ~10% of infections in which viral loads remain sufficiently high for transmission after 10-14 days. In these cases, non-sustained innate and/or weak acquired immune responses allow sufficient time for selection of a variant with one or more fitness enhancing non-synonymous mutations. Across a simulated cohort of ~1500 individuals, 5% of transmission risk came from variants with enhanced fitness from nonsynonymous mutations, and 13% of simulated infections accounted for 90% of fitter variant transmission risk. Our results highlight how the timing and interplay of viral and immunological forces within a host create bottlenecks that severely limit between host evolution.
Katherine Owens, Pierce E. Radecki, S. Tempia et al.· bioRxiv· 0 citations
The data uncover a direct, enzyme-based mechanism by which SARS-CoV-2 can suppress influenza virus replication during coinfection and provide a molecular explanation for the sharp, global decline in influenza activity observed during the COVID-19 pandemic.
Liubing Du, Xiaoyu Cai, Zi-Tao Peng et al.· Virologica Sinica· 0 citations
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