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1.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21267288

Résumé

BackgroundDuring a pandemic, estimates of geographic variability in disease burden are important but limited by the availability and quality of data. MethodsWe propose a framework for estimating geographic variability in testing effort, total number of infections, and infection fatality ratio (IFR). Because symptomatic people are more likely to seek testing, we use a noncentral hypergeometric model that accounts for differential probability of positive tests. We apply this framework to the United States (U.S.) COVID-19 pandemic to estimate county-level SARS-CoV-2 IFRs from March 1, 2020 to October 31, 2020. Using data on population size, number of observed cases, number of reported deaths in each U.S. county and state, and number of tests in each U.S. state, we develop a series of estimators to identify the number of SARS-CoV-2 infections and IFRs at the county level. We then perform a simulation and compare the estimated values to simulated values to demonstrate the validity of our approach. FindingsApplying the county-level estimators to the real, unsimulated COVID-19 data spanning March 1, 2020 to October 31, 2020 from across the U.S., we found that IFRs varied from 0 to 0.0273, with an interquartile range of 0.0022 and a median of 0.0018. The estimators for IFRs, number of infections, and number of tests showed high accuracy and precision; for instance, when applied to simulated validation data sets, across counties, Pearson correlation coefficients between estimator means and true values were 0.88, 0.95, and 0.74, respectively. InterpretationWe propose an estimation framework that can be used to identify area-level variation in IFRs and performs well to estimate county-level IFRs in the U.S. COVID-19 pandemic.

2.
Preprint Dans Anglais | bioRxiv | ID: ppbiorxiv-468228

Résumé

In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like (3CLpro) protease can cleave human immune signaling proteins, like NF-{kappa}B Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.14 [A] resolution crystal structure of 3CLpro C145S bound to NEMO226-235 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro- NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for in the pathology of COVID-19.

3.
Preprint Dans Anglais | bioRxiv | ID: ppbiorxiv-454981

Résumé

The SARS-CoV-2 pandemic recently entered an alarming new phase with the emergence of the variants of concern (VOC) and understanding their biology is paramount to predicting future ones. Current efforts mainly focus on mutations in the spike glycoprotein (S), but changes in other regions of the viral proteome are likely key. We analyzed more than 900,000 SARS-CoV-2 genomes with a computational systems biology approach including a haplotype network and protein structural analyses to reveal lineage-defining mutations and their critical functional attributes. Our results indicate that increased transmission is promoted by epistasis, i.e., combinations of mutations in S and other viral proteins. Mutations in the non-S proteins involve immune-antagonism and replication performance, suggesting convergent evolution. Furthermore, adaptive mutations appear in geographically disparate locations, suggesting that either independent, repeat mutation events or recombination among different strains are generating VOC. We demonstrate that recombination is a stronger hypothesis, and may be accelerating the emergence of VOC by bringing together cooperative mutations. This emphasizes the importance of a global response to stop the COVID-19 pandemic.

4.
Preprint Dans Anglais | bioRxiv | ID: ppbiorxiv-028712

Résumé

Using a Systems Biology approach, we integrated genomic, transcriptomic, proteomic, and molecular structure information to provide a holistic understanding of the COVID-19 pandemic. The expression data analysis of the Renin Angiotensin System indicates mild nasal, oral or throat infections are likely and that the gastrointestinal tissues are a common primary target of SARS-CoV-2. Extreme symptoms in the lower respiratory system likely result from a secondary-infection possibly by a comorbidity-driven upregulation of ACE2 in the lung. The remarkable differences in expression of other RAS elements, the elimination of macrophages and the activation of cytokines in COVID-19 bronchoalveolar samples suggest that a functional immune deficiency is a critical outcome of COVID-19. We posit that using a non-respiratory system as a major pathway of infection is likely determining the unprecedented global spread of this coronavirus. One Sentence SummaryA Systems Approach Indicates Non-respiratory Pathways of Infection as Key for the COVID-19 Pandemic

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