Coronaviruses: Pandemic SARS-CoV-2

Springer eBooks, Год журнала: 2024, Номер unknown, С. 1 - 79

Опубликована: Дек. 18, 2024

Язык: Английский

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ACE-2 Blockade & TMPRSS2 Inhibition Mitigate SARS-CoV-2 Severity Following Cigarette Smoke Exposure in Airway Epithelial Cells In Vitro

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 24, 2024

Cigarette smoking is associated with COVID-19 prevalence and severity, but the mechanistic basis for how alters SARS-CoV-2 pathogenesis unknown. A potential explanation that expression of cellular receptor point entry, angiotensin converting enzyme-2 (ACE-2), its cofactors including transmembrane protease serine 2 (TMPRSS2). We investigated impact cigarette on ACE-2, TMPRSS2, other known infection resultant effects severity in vitro. smoke extract (CSE) exposure increased ACE-2 TMPRSS2 mRNA compared to air control ferret airway cells, Calu-3 primary human bronchial epithelial (HBE) cells derived from normal COPD donors. CSE-exposed inoculated had a significantly higher intracellular viral load versus vehicle-exposed cells. Likewise, CSE-exposure both replication HBE over vehicle control. Apoptosis was CSE-exposed, SARS-CoV-2-infected Knockdown via an antisense oligonucleotide (ASO) reduced augmented by co-administration camostat mesylate block activity. Smoking increases upregulation ACE2 TMPRSS2.

Язык: Английский

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Computational Modeling Insights into Extreme Heterogeneity in COVID-19 Nasal Swab Data

Viruses, Год журнала: 2023, Номер 16(1), С. 69 - 69

Опубликована: Дек. 30, 2023

Throughout the COVID-19 pandemic, an unprecedented level of clinical nasal swab data from around globe has been collected and shared. Positive tests have consistently revealed viral titers spanning six orders magnitude! An open question is whether such extreme population heterogeneity unique to SARS-CoV-2 or possibly generic respiratory infections. To probe this question, we turn computational modeling tract Employing a physiologically faithful, spatially resolved, stochastic model infection, explore statistical distribution human infections in immediate 48 h infection. The spread, heterogeneity, derives variations factors within that are infected host, infectious variant, timing test. Hypothetical include: (1) reported physiological differences between individuals (nasal mucus thickness clearance velocity); (2) kinetics replication, shedding RNA copies arising interactions host variant; (3) time initial cell infection Since positive often pre-symptomatic independent prior vaccination status, assume immune evasion throughout Model simulations generate mean outcomes total shed load cells for each "virtual individual", which define as fixed set parameters above. population" over defined by collecting clinically experimentally guided ranges full (2). This establishes model-generated database" every individual, then compare with test data. Support efficacy comes sampling dynamics virtual database, reproduces six-order-of-magnitude heterogeneity. However, goal study answer deeper biological question. What impact on early due individual feature virus-cell kinetic mechanism? global analysis methods applied database sample across entire de-correlate (i.e., isolate) dynamic outcome sensitivities parameter. These predict dominant, indeed exponential, driver latency (from moment until onset shedding). rate phase strong, but not Furthermore, unknown relative equally dominant contributor since loads grow undetectable levels more than magnitude h.

Язык: Английский

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Mucociliary Clearance Augmenting Drugs Block SARS-Cov-2 Replication in Human Airway Epithelial Cells

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Фев. 1, 2023

Abstract The coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 the infection and destruction ciliated respiratory cells, which perpetuates dissemination disrupts protective mucociliary transport (MCT) function, an innate defense tract. Thus, drugs that augment MCT could improve barrier function airway epithelium, reduce viral replication and, ultimately, outcomes. We tested five agents known to increase through distinct mechanisms for activity against using a model epithelial cells terminally differentiated in air/liquid interphase. Three mucoactive compounds showed significant inhibitory replication. An archetype agent, ARINA-1, blocked therefore cell injury, thus, it was further studied biochemical, genetic biophysical methods ascertain mechanism action via improvement MCT. ARINA-1 antiviral dependent on enhancing cellular response, since terminal differentiation, intact ciliary expression motion required ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we cilia movement regulation redox state intracellular environment, benefited Our study indicates Intact reduces infection, its pharmacologic activation may be effective as anti-COVID-19 treatment.

Язык: Английский

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Global Sensitivity Analysis of the Onset of Nasal Passage Infection by SARS-CoV-2 With Respect to Heterogeneity in Host Physiology and Host Cell-Virus Kinetic Interactions

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 6, 2023

Abstract Throughout the COVID-19 pandemic, positive nasal swab tests have revealed dramatic population heterogeneity in viral titers spanning 6 orders-of-magnitude. Our goal here is to probe potential drivers of infection outcome sensitivity arising from (i) physiological between hosts and (ii) host-variant detailed kinetics cell replication. Toward this goal, we apply global methods (Partial Rank Correlation Coefficient analysis Latin Hypercube Sampling) a physiologically faithful, stochastic, spatial model inhaled SARS-CoV-2 exposure human respiratory tract. We focus on passage as primary origin site clinical testing, simulate dynamic progression shed load infected cells immediate 48 hours post infection. impose immune evasion, i.e., suppressed protection, based preponderance evidence that infections occur rapidly exposure, largely independent status. Global provide de-correlated sensitivities each source within-host heterogeneity, including at 12, 24, 36, The results reveal rank-ordering early infection, providing insights into population-scale diversity during pandemic. While SARS-CoV-2, are applicable any virus

Язык: Английский

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