ABSTRACT
A series of SARS-CoV-2 variants of concern (VOCs) have evolved in humans during the COVID-19 pandemic: Alpha, Beta, Gamma, Delta, and Omicron. Here, we used global proteomic and genomic analyses during infection to understand the molecular responses driving VOC evolution. We discovered VOC-specific differences in viral RNA and protein expression levels, including for N, Orf6, and Orf9b, and pinpointed several viral mutations responsible. An analysis of the host response to VOC infection and comprehensive interrogation of altered virus-host protein-protein interactions revealed conserved and divergent regulation of biological pathways. For example, regulation of host translation was highly conserved, consistent with suppression of VOC replication in mice using the translation inhibitor plitidepsin. Conversely, modulation of the host inflammatory response was most divergent, where we found Alpha and Beta, but not Omicron BA.1, antagonized interferon stimulated genes (ISGs), a phenotype that correlated with differing levels of Orf6. Additionally, Delta more strongly upregulated proinflammatory genes compared to other VOCs. Systematic comparison of Omicron subvariants revealed BA.5 to have evolved enhanced ISG and proinflammatory gene suppression that similarly correlated with Orf6 expression, effects not seen in BA.4 due to a mutation that disrupts the Orf6-nuclear pore interaction. Our findings describe how VOCs have evolved to fine-tune viral protein expression and protein-protein interactions to evade both innate and adaptive immune responses, offering a likely explanation for increased transmission in humans.
Subject(s)
Infections , COVID-19ABSTRACT
The COVID-19 pandemic highlighted the lack of understanding around effective public health interventions to curtail the spread of an emerging respiratory virus. Here, we examined the public health approaches implemented by each state to limit the spread and burden of COVID-19. Our analysis revealed that stronger statewide interventions positively correlated with fewer COVID-19 deaths, but some neighboring states with distinct intervention strategies had similar SARS-CoV-2 case trajectories. Additionally, more than two weeks is needed to observe an impact on SARS-CoV-2 cases after an intervention is implemented. These data provide a critical framework to inform future interventions during emerging pandemics.
Subject(s)
COVID-19ABSTRACT
At the start of the COVID-19 pandemic, most US K-12 schools shutdown and millions of students began remote learning. By September 2020, little guidance had been provided to school districts to inform fall teaching. This indecision led to a variety of teaching postures within a given state. In this report we examine Ohio school districts in-depth, to address whether on-premises teaching impacted COVID-19 disease outcomes in that community. We observed that counties with on-premises teaching had more cumulative deaths at the end of fall semester than counties with predominantly online teaching. To provide a measure of disease progression, we developed an observational disease model and examined multiple possible confounders, such as population size, mobility, and demographics. Examination of micropolitan counties revealed that the progression of COVID-19 disease was faster during the fall semester in counties with predominantly on-premises teaching. The relationship between increased disease prevalence in counties with on-premises teaching was not related to deaths at the start of the fall semester, population size, or the mobility within that county. This research addresses the critical question whether on-premises schooling can impact the spread of epidemic and pandemic viruses and will help inform future public policy decisions on school openings.