Intranasally administrated fusion-inhibitory lipopeptides block SARS-CoV-2 infection in mice and enable long-term protective immunity

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Jan. 15, 2025

Abstract We have assessed antiviral activity and induction of protective immunity fusion-inhibitory lipopeptides derived from the C-terminal heptad-repeat domain SARS-CoV-2 spike glycoprotein in transgenic mice expressing human ACE2 (K18-hACE2). The block infection cell lines lung-derived organotypic cultures. Intranasal administration allows maintenance homeostatic transcriptomic immune profile lungs, prevents body-weight loss, decreases viral load shedding, protects death caused by variants. Prolonged high-dose has neither adverse effects nor impairs peptide efficacy subsequent challenges. peptide-protected develop cross-reactive neutralizing antibodies against both used for initial recently circulating variants, are completely protected a second lethal infection, suggesting that they developed SARS-CoV-2-specific immunity. This strategy provides an additional approach global effort COVID-19 may contribute to development rapid responses emerging pathogenic viruses.

Language: Английский

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Prediction of COVID-19 mortality using machine learning strategies and a large-scale panel of plasma inflammatory proteins: A cohort study

Medicina Intensiva (English Edition), Journal Year: 2025, Volume and Issue: unknown, P. 502200 - 502200

Published: April 1, 2025

Language: Английский

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The Delta SARS-CoV-2 Variant of Concern Induces Distinct Pathogenic Patterns of Respiratory Disease in K18-hACE2 Transgenic Mice Compared to the Ancestral Strain from Wuhan

mBio, Journal Year: 2022, Volume and Issue: 13(3)

Published: April 14, 2022

SARS-CoV-2 variants, with the threat of increased transmissibility, infectivity, and immune escape, continue to emerge as COVID-19 pandemic progresses. Detailing pathogenesis disease caused by such Delta, is essential better understand clinical emerging variants associated disease.

Language: Английский

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A SARS-CoV-2-Related Virus from Malayan Pangolin Causes Lung Infection without Severe Disease in Human ACE2-Transgenic Mice

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(2)

Published: Jan. 23, 2023

Coronavirus disease 2019 (COVID-19), which is caused by the novel coronavirus severe acute respiratory syndrome 2 (SARS-CoV-2), most emerging infectious in current century. The discovery of SARS-CoV-2-related coronaviruses (SARSr-CoV-2) bats and pangolins South Asian countries indicates that SARS-CoV-2 likely originated from wildlife. To date, two SARSr-CoV-2 strains have been isolated seized Guangxi Guangdong customs agency China, respectively. However, it remains unclear whether these viruses cause animal models they pose a transmission risk to humans. In this study, we investigated biological features strain smuggled Malayan pangolin (Manis javanica) captured agency, termed MpCoV-GX, terms receptor usage, cell tropism, pathogenicity wild-type BALB/c mice, human angiotensin-converting enzyme (ACE2)-transgenic ACE2 knock-in mice. We found MpCoV-GX can utilize humans, pangolins, civets, bats, pigs, mice for entry infect lines derived monkeys, minks, pigs. virus could three mouse but showed limited pathogenicity, with mild peribronchial perivascular inflammatory infiltration observed lungs. Our results suggest has potential interspecies infection, its Future surveillance among wildlife hosts needed monitor variants may higher spillover risk. IMPORTANCE SARS-CoV-2, spilled over wildlife, third highly pathogenic coronavirus. Being transmissible, perpetuating pandemic continuously posing threat global public health. Several identified since outbreak. It therefore important assess their crossing species barriers better understanding future emergence. work, pangolin, named MpCoV-GX. 7 variety mammalian species. expressing without causing disease. These findings cross-species highlight need further other hosts.

Language: Английский

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Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice

mSphere, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 2, 2023

The COVID-19 pandemic, caused by SARS-CoV-2, is still significantly impacting health care systems around the globe. Refined animal models are needed to study SARS-CoV-2 pathogenicity as well efficacy of vaccines and therapeutics.

Language: Английский

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SARS-CoV-2 rapidly evolves lineage-specific phenotypic differences when passaged repeatedly in immune-naïve mice

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 16, 2024

Abstract The persistence of SARS-CoV-2 despite the development vaccines and a degree herd immunity is partly due to viral evolution reducing vaccine treatment efficacy. Serial infections wild-type (WT) in Balb/c mice yield mouse-adapted strains with greater infectivity mortality. We investigate if passaging unmodified B.1.351 (Beta) B.1.617.2 (Delta) 20 times K18-ACE2 mice, expressing human ACE2 receptor, BSL-3 laboratory without selective pressures, drives health-relevant lineage-dependent. Late-passage virus causes more severe disease, at organism lung tissue scales, late-passage Delta demonstrating antibody resistance interferon suppression. This co-occurs de novo spike S371F mutation, linked both traits. S371F, an Omicron-characteristic co-inherited E1182G per Nanopore sequencing, existing different within-sample variants others. Both are mammalian GOLGA7 ZDHHC5 interactions, which mediate viral-cell entry antiviral response. study demonstrates SARS-CoV-2’s tendency evolve phenotypic consequences, its varying by lineage, suggests non-dominant quasi-species contribution.

Language: Английский

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Soluble Angiotensin-Converting Enzyme 2 Protein Improves Survival and Lowers Viral Titers in Lethal Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection with the Delta Variant

Cells, Journal Year: 2024, Volume and Issue: 13(3), P. 203 - 203

Published: Jan. 23, 2024

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme (ACE2) as its main receptor for cell entry. We bioengineered a soluble ACE2 protein termed 618-DDC-ABD that has increased binding to SARS-CoV-2 and prolonged duration of action. Here, we investigated the protective effect this when administered intranasally k18-hACE2 mice infected with aggressive Delta variant. were variant by inoculation lethal dose (2 × 104 PFU). (10 mg/kg) or PBS was six hours prior 24 48 h post-viral inoculation. All animals in control group succumbed disease on day seven post-infection (0% survival), whereas, contrast, there only one casualty received (90% survival). Mice had minimal assessed using clinical score stable weight, both brain lung viral titers markedly reduced. These findings demonstrate efficacy decoy an extended action protecting against Together previous work, these underline universal potential current future emerging variants.

Language: Английский

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Virulence Profiles of Wild-Type, P.1 and Delta SARS-CoV-2 Variants in K18-hACE2 Transgenic Mice

Viruses, Journal Year: 2023, Volume and Issue: 15(4), P. 999 - 999

Published: April 19, 2023

Since December 2019, the world has been experiencing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and we now face emergence of several variants. We aimed to assess differences between wild-type (Wt) (Wuhan) strain P.1 (Gamma) Delta variants using infected K18-hACE2 mice. The clinical manifestations, behavior, virus load, pulmonary capacity, histopathological alterations were analyzed. P.1-infected mice showed weight loss more manifestations than Wt Delta-infected capacity was reduced in compared other groups. Pulmonary histological findings demonstrated that a aggressive disease generated virus. quantification SARS-CoV-2 viral copies varied greatly among although it higher on day death. Our data revealed with variant develop infectious those variants, despite significant heterogeneity

Language: Английский

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COVID-19 symptom severity and duration among outpatients, July 2021-May 2023: The PROTECT observational study

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(2), P. e0314518 - e0314518

Published: Feb. 21, 2025

Introduction With the emergence of new SARS-CoV-2 variants has come significant variations in disease manifestation, severity, and duration non-hospitalized infected patients. To characterize symptom patterns risk factors associated with severity duration, COVID-19 influenza-like illness (ILI) outpatients their contacts were enrolled at two sites United States America one site Thailand. Methods infection was confirmed enrollment a positive antigen or PCR test. Baseline demographics medical histories collected from participants daily self-reported questionnaires obtained to assess duration. Risk determined by multivariate logistic regression Cox proportional hazards model. Results Two hundred forty meeting eligibility criteria enrolled, including 174 cases (9% Delta 90% Omicron), 33 ILI cases, 34 healthy contacts. had shorter median 9.0 (95% CI, 8.0–11.0) days than participants. Infection variant resulted longer alleviation period compared Omicron variant. The most commonly reported symptoms among nasal chest/respiratory domains FLU-PRO Plus. Participants more overall, significantly affecting eyes senses reported. 55% SARS-CoV-2-positive reached negative N1 Ct value day 14 study time point. No for moderate severe identified this outpatient cohort. Male sex Conclusion Symptom manifestation varied variants. Few increased

Language: Английский

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Deficiency in platelet 12-lipoxygenase exacerbates inflammation and disease severity during SARS-CoV-2 infection

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(12)

Published: March 18, 2025

Platelets, known for maintaining blood balance, also participate in antimicrobial defense. Upon severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, platelets become hyperactivated, releasing molecules such as cytokines, granule contents, and bioactive lipids. The key effector biolipids produced by include 12-hydroxyeicosatetraenoic acid (12-HETE) 12-hydroxyeicosatrienoic (12-HETrE), 12-lipoxygenase (12-LOX), prostaglandins thromboxane, cyclooxygenase-1. While prostaglandin E2 thromboxane B2 were previously associated with lung inflammation severe COVID-19, the role of platelet 12-LOX SARS-CoV-2 infection remains unclear. Using mice deficient platelets’ 12-LOX, we report that resulted higher characterized histopathological tissue analysis, increased leukocyte infiltrates, cytokine production relative to wild-type mice. In addition, distinct transcriptomic changes, including alterations NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) inflammasome-related gene expression, observed. Mass spectrometry lipidomic analysis 12-LOX-deficient-infected revealed significant changes lipid content, reduced levels 12-HETrE inversely correlated disease severity. Finally, deficiency was morbidity lower survival rates wild type (WT) Overall, this study highlights complex interplay between 12-LOX-related metabolism inflammatory responses during infection. findings provide valuable insights into potential therapeutic targets aimed at mitigating outcomes, emphasizing pivotal enzymes host response viral infections.

Language: Английский

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