Computational Modeling Insights into Extreme Heterogeneity in COVID-19 Nasal Swab Data DOI Creative Commons
Leyi Zhang, Han Cao,

Karen Medlin

и другие.

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

Neutrophils play a major role in the destruction of the olfactory epithelium during SARS-CoV-2 infection in hamsters DOI Open Access

Clara Bourgon,

Audrey St Albin,

Ophélie Ando-Grard

и другие.

Cellular and Molecular Life Sciences, Год журнала: 2022, Номер 79(12)

Опубликована: Дек. 1, 2022

Язык: Английский

Процитировано

24
Live imaging of airway epithelium reveals that mucociliary clearance modulates SARS-CoV-2 spread DOI Creative Commons
Mark E. Becker, Laura Martin‐Sancho, Lacy M. Simons

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 2, 2024

SARS-CoV-2 initiates infection in the conducting airways, where mucociliary clearance inhibits pathogen penetration. However, it is unclear how impacts spread after established. To investigate viral at this site, we perform live imaging of infected differentiated primary human bronchial epithelium cultures for up to 12 days. Using a fluorescent reporter virus and markers cilia mucus, longitudinally monitor mucus motion, ciliary infection. Infected cell numbers peak 4 days post infection, forming characteristic foci that tracked movement. Inhibition MCC using physical genetic perturbations limits foci. Later deteriorates. Increased secretion accompanies motion defects, but vectorial resume removal, suggesting may mediate deterioration. Our work shows while can facilitate initial subsequent decreases inhibit spread, revealing complex interplay between MCC.

Язык: Английский

Процитировано

4
COVID-19 Causes Ciliary Dysfunction as Demonstrated by Human Intranasal Micro-Optical Coherence Tomography Imaging DOI Creative Commons
Kadambari Vijaykumar, Hui Min Leung,

Amilcar Barrios

и другие.

American Journal of Respiratory Cell and Molecular Biology, Год журнала: 2023, Номер 69(5), С. 592 - 595

Опубликована: Ноя. 1, 2023

Язык: Английский

Процитировано

9
Randomised, Placebo-Controlled, Double-Blind Trial to Assess Efficacy and Safety of ELOM-080 in Outpatients with COVID-19 DOI Creative Commons
Michael Dreher, Hans Erik Heier,

Andrea Kienle-Gogolok

и другие.

Advances in Therapy, Год журнала: 2025, Номер 42(2), С. 1237 - 1250

Опубликована: Янв. 15, 2025

Incidences of infections with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) are still high and treatment guidelines lack specific recommendations for outpatients Coronavirus-induced disease 2019 (COVID-19). Phytomedicine ELOM-080, an enhancer mucociliary clearance (MCC), showed benefits as add-on therapy in hospitalised COVID-19 patients. This randomised, double-blind, placebo-controlled proof-of-concept study investigated whether mild to moderate acute symptomatic would benefit from a 14-day ELOM-080 regard potential early effects on cough further typical symptoms. Outpatients documented symptom severity count coughs daily basis. Investigators safety during the visits. missed its primary objective, which was reduction coughing fits comparison placebo treatment. In analysis, no relevant differences were observed between arms. Data all randomised patients broad heterogeneity in, e.g., time courses fits, affected both magnitude timing changes baseline. However, post hoc analyses population suspected dysfunctional MCC revealed that significantly benefitted terms (p = 0.0070), difficulty breathing exertion 0.0252), earlier remission symptoms by 1-3 days. We have shown ELOM-080. These results might be clinical importance, up now has obtained market approval COVID-19. EudraCT number: 2022-003478-22.

Язык: Английский

Процитировано

0
Betrayal From the Core: Centriolar and Cytoskeletal Subversion by Infectious Pathogens DOI Open Access

Himanshi Amita,

Zidhan Subair,

Tulasiram Mora

и другие.

Cytoskeleton, Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

Microbes and parasites have evolved several means to evade usurp the host cellular machinery mediate pathogenesis. Being major microtubule-organizing center (MTOC) of cell, centrosome is targeted by multiple viral nonviral pathogens their assembly trafficking within cell. This review examines consequence such targeting associated cytoskeletal machinery. We also amassed a substantial body evidence viruses utilizing cilia airway epithelium infection hijacking for efficient entry, replication, egress. While infections been demonstrated induce structural, functional, numerical aberrations in centrosomes, ciliary dysfunction, current literature increasingly supports notion pro-viral role these organelles. Although less explored, impact bacterial parasitic on structures has addressed very briefly. Mechanistically, molecular pathways responsible effects remain largely uncharacterized many instances. Future research focusing centriolar triad comprising centrosome, cilia, satellites will undoubtedly provide vital insights into tactics employed infectious agents subvert centriole cytoskeleton-based

Язык: Английский

Процитировано

0
Optical Imaging of Cilia in the Head and Neck DOI Open Access
Elizabeth Lee,

Lidek Chou,

Zhongping Chen

и другие.

Journal of Clinical Medicine, Год журнала: 2025, Номер 14(6), С. 2059 - 2059

Опубликована: Март 18, 2025

Background/Objectives: Cilia are hair-like organelles with various mechanosensory and chemosensory functions. In particular, motile cilia generate directional fluid flow important for multiple processes. Motile ciliopathies have serious clinical implications, including developmental respiratory disorders. Evaluating the most suitable imaging methods studying ciliary structure function has great significance. Methods: Here, we provide an overview of function, modalities, applications in ciliopathic diseases. Results: Optical become a crucial tool providing high-resolution, non-invasive capabilities that valuable vivo applications. coherence tomography (OCT) is well suited visualization anatomy quantitative studies microfluidic flow. Conclusions: A deeper understanding biology can lead to novel approaches diagnosing, treating, monitoring ciliopathies, contributing more effective individualized care.

Язык: Английский

Процитировано

0
DNA methylation changes during acute COVID-19 are associated with long-term transcriptional dysregulation in patients’ airway epithelial cells DOI Creative Commons
Marey Messingschlager, Sebastian D. Mackowiak, Maria Theresa Vöelker

и другие.

EMBO Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 21, 2025

Abstract Molecular changes underlying the persistent health effects after SARS-CoV-2 infection remain poorly understood. To discern gene regulatory landscape in upper respiratory tract of COVID-19 patients, we performed enzymatic DNA methylome and single-cell RNA sequencing nasal cells patients ( n = 19, scRNA-seq 14) controls 14, 10). In addition, resampled a subset these for transcriptome analyses at 3 7) 12 months 5) post followed expression differentially regulated genes over time. Genome-wide methylation analysis revealed 3112 methylated regions between controls. Hypomethylated affected immune genes, while hypermethylated were associated with governing ciliary function. These not only downregulated acute phase disease but sustained repressed up to ciliated cells. Validation an independent cohort collected 6 15) indicated symptom-dependent transcriptional repression genes. We therefore propose that hypermethylation observed may exert long-term effect on expression, possibly contributing post-acute sequelae.

Язык: Английский

Процитировано

0
A single intranasal administration of AdCOVID protects against SARS-CoV-2 infection in the upper and lower respiratory tracts DOI Creative Commons
Michael D. Schultz, John J. Suschak, Davide Botta

и другие.

Human Vaccines & Immunotherapeutics, Год журнала: 2022, Номер 18(6)

Опубликована: Окт. 4, 2022

The coronavirus disease 2019 (COVID-19) pandemic has illustrated the critical need for effective prophylactic vaccination to prevent spread of severe acute respiratory syndrome 2 (SARS-CoV-2). Intranasal is an attractive approach preventing COVID-19 as nasal mucosa site initial SARS-CoV-2 entry and viral replication prior aspiration into lungs. We previously demonstrated that a single intranasal administration candidate adenovirus type 5-vectored vaccine encoding receptor-binding domain spike protein (AdCOVID) induced robust immunity in both airway periphery, completely protected K18-hACE2 mice from lethal challenge. Here we show AdCOVID limits cavity mice. also induces sterilizing lungs reflected by absence infectious virus. Finally, prevents pathological damage These data not only tract, but it virus-induced inflammation immunopathology following infection.

Язык: Английский

Процитировано

13
Mucociliary clearance augmenting drugs block SARS-CoV-2 replication in human airway epithelial cells DOI Creative Commons
Javier Campos, Courtney Fernandez Petty, Marina Mazur

и другие.

AJP Lung Cellular and Molecular Physiology, Год журнала: 2023, Номер 324(4), С. L493 - L506

Опубликована: Фев. 21, 2023

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 were required ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we cilia movement regulation redox state intracellular environment, benefited Our study indicates reduces infection, its pharmacologic activation may be effective as anti-COVID-19 treatment.

Язык: Английский

Процитировано

7
Community-acquired bacterial coinfections and COVID-19 DOI
Michael J. Patton, Amit Gaggar, Matthew Might

и другие.

Physiological Reviews, Год журнала: 2023, Номер 104(1), С. 1 - 21

Опубликована: Авг. 17, 2023

Язык: Английский

Процитировано

7