Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice DOI Creative Commons
Agnes Carolin, Kexin Yan, Cameron Bishop

et al.

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(11), P. e0302344 - e0302344

Published: Nov. 12, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in disease, often characterised by a 'cytokine storm' and the associated distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout course of infection. Although blood biomarkers disease well studied, less understood inflammatory signatures lung tissues silent infections, wherein infection inflammation rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq histological analyses lungs over time an omicron BA.1/K18-hACE2 mouse model, displays these latter features. robust was evident at days post (dpi), viral RNA largely cleared 10 dpi. Acute showed slightly different pattern cytokine compared models, where much diminished 30 dpi absent 66 Cellular deconvolution identified significantly increased abundance scores for number anti-inflammatory pro-resolution cell types 5/10 These included type II innate lymphoid cells, T regulatory interstitial macrophages. Genes whose expression trended downwards 2-66 were pathways. upward during this period recovery ciliated AT2 AT1 transition, reticular fibroblasts indicating return homeostasis. Very few differentially expressed host genes dpi, suggesting near complete parallels between subclinical humans those observed model discussed reference concept "protective inflammation".

Language: Английский

SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids DOI Creative Commons
Romal Stewart, Kexin Yan, Sevannah A. Ellis

et al.

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 23, 2023

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation retained for later like BA.5 and XBB remains controversial. We show that isolates were significantly more pathogenic in K18-hACE2 mice than a isolate, showing increased neurotropic potential, resulting fulminant brain infection mortality, similar seen original ancestral isolates. also infected human cortical organoids greater extent In brains mice, neurons main target infection, neuronal progenitor cells immature infected. results herein suggest evolving may have increasing potential.

Language: Английский

Citations

26
Intranasal liposomal remdesivir induces SARS-CoV-2 clearance in K18-hACE2 mice and ensures survival DOI
Sabrina Mendes, Lays Cordeiro Guimarães, Leonardo Camilo de Oliveira

et al.

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 379, P. 558 - 573

Published: Jan. 24, 2025

Language: Английский

Citations

1
Bioluminescence imaging reveals enhanced SARS-CoV-2 clearance in mice with combinatorial regimens DOI Creative Commons
Irfan Ullah, Fanny Escudié, Ivan Scandale

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(3), P. 109049 - 109049

Published: Jan. 30, 2024

Language: Английский

Citations

6
Severe Acute Respiratory Syndrome Coronavirus 2 Variant Infection Dynamics and Pathogenesis in Transgenic K18-hACE2 and Inbred Immunocompetent C57BL/6J Mice DOI Creative Commons
H. Liu, Brianna M. Ramirez, Talia S. Wong

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(4), P. 500 - 500

Published: March 30, 2025

The global impact of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), persists in part due to emergence new variants. Understanding variant-specific infection dynamics and pathogenesis murine models is crucial for identifying phenotypic changes guiding development countermeasures. To address limitations earlier studies that investigated only a few variants or used small sample sizes, we evaluated clinical disease, kinetics, viral titers, cellular localization, histopathologic lungs brains transgenic B6.Cg-Tg(K18-ACE2)2Prlmn/J (“K18”) corresponding genetic control (C57BL/6J) mice expressing human angiotensin-converting enzyme (hACE2). Six SARS-CoV-2 were assessed: B.1 (WA1-like), alpha, beta, delta, omicron, omicron XBB.1.5, using cohorts ≥18 mice. Following intranasal inoculation with B.1, delta variants, K18 experienced rapid weight loss reached euthanasia criteria 5–6 days post-inoculation (dpi). In contrast, inoculated both recovered their starting within 4–6 dpi. Infectious was detected oropharynx at 1 and2 dpi, 2, 4, 6 brain 4 dpi all except omicron. nucleoprotein detected, interstitial pneumonia varying severity observed infected Brain lesions identified As express hACE2 brain—a feature not present humans—we also compared three those mouse-adapted WA1 strain C57BL/6J lacking ACE2 gene. did experience lethal exhibited milder pneumonia, had no evidence neuroinvasion despite similar kinetics These findings demonstrate contrasting phenotypes across two reduced tropism pathology models. This comprehensive analysis mouse provides valuable insights model variant selection future studies.

Language: Английский

Citations

0
Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice DOI Creative Commons
Agnes Carolin, Kexin Yan, Cameron Bishop

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 13, 2024

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in disease, often characterised by a ‘cytokine storm’ and the associated distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout course of infection. Although blood biomarkers disease well studied, less understood inflammatory signatures lung tissues silent infections, wherein infection inflammation rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq histological analyses lungs over time an omicron BA.1/K18-hACE2 mouse model, displays these latter features. robust was evident at days post (dpi), viral RNA largely cleared 10 dpi. Acute showed slightly different pattern cytokine compared models, where much diminished 30 dpi absent 66 Cellular deconvolution identified significantly increased abundance scores for number anti-inflammatory pro-resolution cell types 5/10 These included type II innate lymphoid cells, T regulatory interstitial macrophages. Genes whose expression trended downwards – were pathways. upward during this period recovery ciliated AT2 AT1 transition, reticular fibroblasts indicating return homeostasis. Very few differentially expressed host genes dpi, suggesting near complete parallels between subclinical humans those observed model discussed reference concept “protective inflammation”.

Language: Английский

Citations

3
Development of a mutant aerosolized ACE2 that neutralizes SARS-CoV-2 in vivo DOI Creative Commons
Daniel L. Kober, Marley C. Caballero Van Dyke,

Jennifer L. Eitson

et al.

mBio, Journal Year: 2024, Volume and Issue: 15(6)

Published: May 21, 2024

The rapid evolution of SARS-CoV-2 variants highlights the need for new therapies to prevent disease spread. SARS-CoV-2, like SARS-CoV-1, uses human cell surface protein angiotensin-converting enzyme 2 (ACE2) as its native receptor. Here, we design and characterize a mutant ACE2 that enables affinity purification dimeric by altering active site autoproteolytic digestion C-terminal His

Language: Английский

Citations

1
Lisinopril increases lung ACE2 levels and SARS-CoV-2 viral load and decreases inflammation but not disease severity in experimental COVID-19 DOI Creative Commons

Yasmin da Silva-Santos,

Roberta Liberato Pagni,

Thaís Helena Martins Gamon

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: July 12, 2024

COVID-19 causes more severe and frequently fatal disease in patients with pre-existing comorbidities such as hypertension heart disease. SARS-CoV-2 virus enters host cells through the angiotensin-converting enzyme 2 (ACE2), which is fundamental maintaining arterial pressure renin-angiotensin system (RAS). Hypertensive commonly use medications inhibitors (ACEi), can modulate expression of ACE2 and, therefore, potentially impact susceptibility severity infection. Here we assessed whether treatment ACE2-humanized (K18-hACE2) mice ACEi Lisinopril affects lung levels outcome experimental COVID-19. K18-hACE2 were treated for 21 days 10 mg/kg then infected 5 PFU (Wuhan strain). Body weight, clinical score, respiratory function, survival, levels, viral load, histology, cytokine (IL-6, IL-33, TNF-α) assessed. Mice showed increased lungs. Infection led to massive decrease at 3 post-infection (dpi) untreated animals, but Lisinopril-treated a fast recovery (5dpi) levels. Higher remarkably higher loads 6/7dpi. decreased pro-inflammatory cytokines IL-6 TNF-α serum lungs Marginal improvements body score survival observed mice. No differences between function histology. both deleterious (higher loads) beneficial (anti-inflammatory probably anti-constrictory anti-coagulant) effects These seem compensate each other, resulting marginal terms animals.

Language: Английский

Citations

1
Intranasal liposomal angiotensin-(1-7) administration reduces inflammation and viral load in the lungs during SARS-CoV-2 infection in K18-hACE2 transgenic mice DOI
Sabrina Mendes, Lays Cordeiro Guimarães, Pedro Augusto Carvalho Costa

et al.

Antimicrobial Agents and Chemotherapy, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 29, 2024

ABSTRACT To effectively reduce the health impact of coronavirus disease (COVID-19), it is essential to adopt comprehensive strategies protect individuals from severe acute respiratory syndrome. In that sense, much effort has been devoted discovery and repurposing effective antiviral anti-inflammatory molecules. The endogenous peptide angiotensin-(1-7) [Ang-(1-7)] recently proposed as a promising agent control infections. Liposomes also emerged safe drug carrier system for local delivery lungs. this context, aim study was develop liposomal formulation Ang-(1-7) [LAng (1-7)] investigate its on animal survival well efficacies after intranasal administration in transgenic K18-hACE2 mice infected with SARS-CoV-2. prepared by ethanol injection method, exhibiting mean diameter 100 nm polydispersity index 0.1. Following treatment every 12 hours 5 days, LAng (1-7) extended compared groups received either empty liposomes, free Ang-(1-7), or phosphate-buffered saline. Furthermore, significantly decreased viral load, IL-6 tumor necrosis factor levels Conventional remdesivir parenteral route used positive promoted similar effects, leading improved rates reduced load lungs without significant effects level. conclusion, emerges improve decrease severity infections, such COVID-19.

Language: Английский

Citations

1
Combinatorial Regimens Augment Drug Monotherapy for SARS-CoV-2 Clearance in Mice DOI Open Access
Irfan Ullah, Fanny Escudié, Ivan Scandale

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 1, 2023

Summary Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that evolve to escape spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging evaluate therapeutic efficacy DAAs target RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best followed by molnupiravir favipiravir suppressing viral loads lung. Unlike neutralizing antibody treatment, DAA monotherapy did not eliminate However, targeting two enzymes combining nirmatrelvir resulted superior virus clearance. Furthermore, Caspase-1/4 inhibitor mitigated inflammation lung pathology whereas COVID-19 convalescent plasma yielded rapid clearance 100% survival. Thus, our study provides insights into treatment efficacies other effective combinations bolster arsenal.

Language: Английский

Citations

2
ANÁLISE DA RELAÇÃO SINTOMA-SEQUELA COM VARIANTES DO VÍRUS SARS-COV-2 EM PACIENTES PORTADORES DE COVID LONGA: UMA REVISÃO DESCRITIVA DOI Creative Commons

Andréa Patrícia Marques da Silva,

Fabiana Kelly Roque da Silva,

Rejane Cleide do Nascimento

et al.

Revista Contemporânea, Journal Year: 2024, Volume and Issue: 4(7), P. e5271 - e5271

Published: July 31, 2024

A COVID longa refere-se aos sintomas persistentes após a infecção aguda pelo SARS-CoV-2, incluindo fadiga, dificuldade respiratória, perda de memória, dores musculares e articulares, olfato ou paladar, problemas cardíacos neurológicos, cuja gravidade pode variar entre os indivíduos. Desde o início da pandemia, surgiram várias variantes do como Alfa, Beta, Gama, Delta Ômicron, cada uma impactando forma diferente prevalência natureza das sequelas longa. fase é um fator crucial ser comparado com as em geral, embora variante tipo Delta, acordo estudos, parecem aumentar probabilidade internações hospitalares por COVID-19. Variantes maior transmissibilidade carga viral, elevam devido à novos tropismos evasão resposta imunológica. falta estudos sobre diante sua importância clínica, dificulta diagnóstico, tratamento, compreensão dos mecanismos subjacentes, avaliação impacto na saúde pública formação médica adequada. É necessário investir mais pesquisas para melhorar atendimento, planejar recursos capacitar profissionais essa condição.

Citations

0