SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

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

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Characterisation of a Japanese Encephalitis virus genotype 4 isolate from the 2022 Australian outbreak

npj Viruses, Journal Year: 2024, Volume and Issue: 2(1)

Published: May 10, 2024

Abstract Human infections with the Japanese encephalitis virus (JEV) are a leading cause of viral encephalitis. An unprecedented outbreak JEV genotype 4 was recently reported in Australia, an isolate (JEV NSW/22 ) obtained from stillborn piglet brain. Herein we conduct thorough characterization three different mouse strains and human cortical brain organoids (hBOs), determined ability to be neutralized by sera humans vaccinated IMOJEV. less virulent than FU (genotype 2) Nakayama 3) C57BL/6J mice interferon regulatory factor 7 deficient ( Irf7 −/− mice, infection wild-type knockout murine embryonic fibroblasts indicating is more sensitive type I responses. provide new model for , showing higher viremia levels compared allowing lethal neuroinvasive infection. All were universally Ifnar day 3, histological signs hemorrhage, but no other lesions. There indications protein detected blood vessels, not neurons. isolates showed robust cytopathic organoids, albeit lower . IMOJEV vaccination induced antibodies capable neutralizing although, all strains, cross-neutralization titers declined increasing divergence envelope amino acid sequences. Overall, our study establishes hBO models infection, possible that rarer genotypes. regimens may afford protection against this newly emerged strain, although antibody responses sub-optimal.

Language: Английский

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Microplastics dysregulate innate immunity in the SARS-CoV-2 infected lung

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

Published: May 13, 2024

Introduction Global microplastic (MP) pollution is now well recognized, with humans and animals consuming inhaling MPs on a daily basis, growing body of concern surrounding the potential impacts human health. Methods Using mouse model mild COVID-19, we describe herein effects azide-free 1 μm polystyrene MP beads, co-delivered into lungs SARS-CoV-2 omicron BA.5 inoculum. The effect host response to infection was analysed using histopathology RNA-Seq at 2 6 days post-infection (dpi). Results Although reduced clearance from lung, virus titres viral RNA levels were not significantly affected by MPs, overt MP-associated clinical or histopathological changes observed. However, infected revealed that exposure suppressed innate immune responses dpi increased pro-inflammatory signatures dpi. cytokine profile showed significant correlation ‘cytokine release syndrome’ signature observed in some COVID-19 patients. Discussion findings are consistent recent finding can inhibit phagocytosis apoptotic cells via binding Tim4. They also add literature suggesting dysregulate inflammatory processes specific disease settings.

Language: Английский

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Evolution of ACE2-independent SARS-CoV-2 infection and mouse adaption after passage in cells expressing human and mouse ACE2

Virus Evolution, Journal Year: 2022, Volume and Issue: 8(2)

Published: July 1, 2022

Human

Language: Английский

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Safety concern of recombination between self-amplifying mRNA vaccines and viruses is mitigated in vivo

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(8), P. 2519 - 2534

Published: June 17, 2024

Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is potential for recombination between alphavirus-based SAM and circulating viruses. This theoretical risk needs to assessed regulatory process vaccine approval. Herein, we undertake extensive vitro vivo assessments explore a wide selection alphaviruses coronavirus. were found effectively limit alphavirus co-infection through superinfection exclusion, although some co-replication was still possible. Using sensitive cell-based assays, replication-competent chimeras generated as result rare, but reproducible, RNA events. The displayed no increased fitness cell culture. Viable not detected C57BL/6J, Rag1

Language: Английский

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Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

iScience, Journal Year: 2022, Volume and Issue: 26(1), P. 105748 - 105748

Published: Dec. 6, 2022

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of viral load has passed; however, its underlying mechanisms remain unclear. In present study, analysis alveolar tissue injury markers and epithelial cell death in patients revealed that COVID-19-induced ARDS was characterized necrosis at an early disease stage. Serum levels HMGB-1, one DAMPs released from necrotic cells, were also significantly elevated these patients. Further using a mouse model mimicking showed involved two forms programmed necrosis, namely necroptosis, pyroptosis. Finally, neutralization HMGB-1 attenuated model. Collectively, including necroptosis pyroptosis, predominant form stage subsequent release potential driver ARDS.

Language: Английский

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CCR5/CXCR3 antagonist TAK-779 prevents diffuse alveolar damage of the lung in the murine model of the acute respiratory distress syndrome

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

Published: Feb. 21, 2024

Introduction: The acute respiratory distress syndrome (ARDS), secondary to viral pneumonitis, is one of the main causes high mortality in patients with COVID-19 (novel coronavirus disease 2019)-ongoing SARS-CoV-2 infection- reached more than 0.7 billion registered cases. Methods: Recently, we elaborated a non-surgical and reproducible method unilateral total diffuse alveolar damage (DAD) left lung ICR mice-a publicly available imitation ARDS caused by SARS-CoV-2. Our data read that two C-C chemokine receptor 5 (CCR5) ligands, macrophage inflammatory proteins (MIPs) MIP-1α/CCL3 MIP-1β/CCL4, are upregulated this DAD model up three orders magnitude compared background level. Results: Here, showed nonpeptide compound TAK-779, an antagonist CCR5/CXCR3, readily prevents single injection 2.5 mg/kg. Histological analysis revealed reduced peribronchial perivascular mononuclear infiltration wall lumen alveoli TAK-779-treated animals. Administration TAK-779 decreased 3-5-fold level serum cytokines chemokines animals DAD, including CCR5 ligands MIP-1α/β, MCP-1, CCL5. Computed tomography rapid recovery density volume affected Discussion: pre-clinical suggest effective administration dexamethasone or anti-IL6R therapeutic antibody tocilizumab, which brings novel modality other inhibitors for treatment virus-induced hyperinflammation syndromes, COVID-19.

Language: Английский

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Warmer ambient air temperatures reduce nasal turbinate and brain infection, but increase lung inflammation in the K18-hACE2 mouse model of COVID-19

The Science of The Total Environment, Journal Year: 2022, Volume and Issue: 859, P. 160163 - 160163

Published: Nov. 14, 2022

Warmer climatic conditions have been associated with fewer COVID-19 cases. Herein we infected K18-hACE2 mice housed at the standard animal house temperature of ∼22 °C, or ∼31 which is considered to be thermoneutral for mice. On day 2 post infection, RNA-Seq analyses showed no significant differential gene expression lung in lungs two temperatures, almost identical viral loads and type I interferon responses. There was also difference on 5, but histology clearly elevated inflammatory signatures infiltrates. Thermoneutrality thus promoted inflammation. infection 31 °C reduced nasal turbinates, consistent increased mucociliary clearance warmer ambient temperature. These had virus levels brain, an ensuing amelioration weight loss a delay mortality. air temperatures may reduce upper respiratory track olfactory epithelium, resulting brain infection. Potential relevance anosmia neurological sequelae patients discussed.

Language: Английский

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Monoclonal Antibodies Specific for SARS-CoV-2 Spike Protein Suitable for Multiple Applications for Current Variants of Concern

Viruses, Journal Year: 2022, Volume and Issue: 15(1), P. 139 - 139

Published: Dec. 31, 2022

The global coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) has spawned an ongoing demand for new research reagents and interventions. Herein we describe a panel of monoclonal antibodies raised against SARS-CoV-2. One antibody showed excellent utility immunohistochemistry, clearly staining infected cells in formalin-fixed paraffin embedded lungs brains mice with original omicron variants We demonstrate reactivity to multiple concern using ELISAs use indirect immunofluorescence assays, Western blots, rapid antigen tests. Finally, illustrate ability two reduce significantly viral tissue titers K18-hACE2 transgenic isolate

Language: Английский

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A highly susceptible hACE2-transgenic mouse model for SARS-CoV-2 research

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

Published: Feb. 7, 2024

Several animal models have been used to assist the development of vaccines and therapeutics since COVID-19 outbreak. Due lack binding affinity mouse angiotensin-converting enzyme II (ACE2) S protein severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), increasing susceptibility mice SARS-CoV-2 infection was considered in several ways. Here, we generated a model expressing human ACE2 (hACE2) under control CAG promoter. Overexpression hACE2 did not pose significant effect on weight growth. After inoculation, showed obvious viral replication production inflammation within 7 days, with gradual decrease body until death. Virological testing found that virus can replicate system, small intestine, brain. Additionally, this applied compare two antibody drug candidates, anti-RBD (MW06) CD24-conjugated (mCD24-MW06). Differences antiviral effects between these antibodies be demonstrated when challenge dose invalidates treatment used. This study provided new for studying pathogenesis evaluating potential interventions.

Language: Английский

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