The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response.

Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections. Among these ncRNAs, the long non-coding RNA (lncRNA) family is especially relevant due to their intrinsic functional properties and ubiquitous biological roles. Specific lncRNAs have been recently characterized as modulators of the cellular response during infection of human host cells by single stranded RNA viruses. However, the role of host lncRNAs in the infection by human RNA coronaviruses such as SARS-CoV-2 remains uncharacterized. In the present work, we have performed a transcriptomic study of a cohort of patients with different SARS-CoV-2 viral load. Our results revealed the existence of a SARS-CoV-2 infection-dependent pattern of transcriptional up-regulation in which specific lncRNAs are an integral component. To determine the role of these lncRNAs, we performed a functional correlation analysis complemented with the study of the validated interactions between lncRNAs and RNA-binding proteins (RBPs). This combination of in silico functional association studies and experimental evidence allowed us to identify a lncRNA signature composed of six elements - NRIR, BISPR, MIR155HG, FMR1-IT1, USP30-AS1, and U62317.2 - associated with the regulation of SARS-CoV-2 infection. We propose a competition mechanism between the viral RNA genome and the regulatory lncRNAs in the sequestering of specific RBPs that modulates the interferon response and the regulation of RNA surveillance by nonsense-mediated decay (NMD). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/485903v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@4368c9org.highwire.dtl.DTLVardef@1948201org.highwire.dtl.DTLVardef@e31fd9org.highwire.dtl.DTLVardef@1400805_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstractModel of interactions among lncRNA and cognate RNA-binding proteins in SARS-CoV-2 infection. According to our model, the viral genome can establish direct interactions with three core proteins (DDX3X, UPF1 and IGF2BP2) involved in mRNA metabolism and regulation of the interferon response, which are also components of a SARS-CoV-2 lncRNA-centered regulatory network. The competition between viral RNA and lncRNAs could act as a counteracting factor for the normal function of homeostatic lncRNA-centered regulatory networks, contributing to viral progression and replication. Black arrows depict physical interactions between network components; red arrows represent functional relationships.

COVID-19 infection and vaccination rates in healthcare workers in British Columbia, Canada: A Longitudinal Urban versus Rural Analysis of the Impact of the Vaccine Mandate

PurposeHealthcare workers (HCWs) play a critical role in responding to the COVID-19 pandemic. Early in the pandemic, urban centres were hit hardest globally; rural areas gradually became more impacted. We compared COVID-19 infection and vaccine uptake in HCWs living in urban versus rural locations within, and between, two health authorities in British Columbia (BC), Canada. We also analyzed the impact of a vaccine mandate for HCWs. MethodsWe tracked laboratory-confirmed SARS-CoV-2 infections, positivity rates, and vaccine uptake in 29,021 HCWs in Interior Health (IH) and 24,634 HCWs in Vancouver Coastal Health (VCH), by occupation, age, and home location, comparing to the general population in that region. We then evaluated the impact of infection rates as well as the mandate on vaccination uptake. ResultsBy October 27, 2021, the date that unvaccinated HCWs were prohibited from providing healthcare, only 1.6% in VCH yet 6.5% in IH remained unvaccinated. Rural workers in both areas had significantly higher unvaccinated rates compared with urban dwellers. Over 1,800 workers, comprising 6.4% of rural HCWs and 3.3% of urban HCWs, remained unvaccinated and set to be terminated from their employment. While the mandate prompted a significant increase in second doses, the impact on the unvaccinated was less clear. ConclusionsAs rural areas often suffer from under-staffing, loss of HCWs could have serious impacts on healthcare provision as well as on the livelihoods of unvaccinated HCWs. Greater efforts are needed to understand how to better address the drivers of rural-related vaccine hesitancy as the pandemic continues.

Estimating Unreported Deaths Associated with COVID-19

Efforts to mitigate the spread of coronavirus disease 2019 (COVID-19) in the United States require an accurate understanding of how the epidemic is progressing. The National Center for Health Statistics (NCHS) releases weekly numbers of deaths attributed to a set of select causes, including deaths from COVID-19 in the entire United States (US), by state, and cumulatively for individual counties. Comparing US and state level deaths from select causes recorded in 2020 with values from 2014-2019 identifies a number of differences that exceeded 95% confidence limits on historical mean values, including three states with deaths possibly from COVID-19 in December 2019. Comparing county-level NCHS datasets with county-level data on deaths from COVID-19 compiled by four public pandemic tracking sites suggests that a large number of COVID-19 deaths have not yet been reported to the NCHS. Dividing the numbers of COVID-19 deaths counted by the public tracking sites by the percentage of COVID-19 deaths reported to the NCHS suggests that approximately 20% of all US deaths from Natural Causes, as many as 200,000, may not yet have been reported to the NCHS. Evaluating changes in the fractions of deaths attributed to COVID-19 and other specific causes or nonspecific outcomes during the epidemic, relative to 2020 totals or historical mean values, can provide a valuable perspective on the public health consequences of COVID-19. Significance StatementEstimating total deaths from natural causes using the percentage of natural cause deaths from COVID-19 reported to the CDC and the number of COVID-19 deaths counted by public tracking sites suggests that up to 200,000 deaths from natural causes between 22 April and 15 August, 2020, around 20% of the total recorded as of 26 August, have not yet been reported to the CDC.