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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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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TMEM106B-mediated SARS-CoV-2 infection allows for robust ACE2-independent infection in vitro but not in vivo

Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114921 - 114921

Published: Nov. 1, 2024

Angiotensin-converting enzyme 2 (ACE2) is the primary entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV-2), but ACE2-independent has been observed in vitro strains with spike-E484D substitution. Here, we conduct a whole-genome CRISPR-Cas9 knockout screen using SARS-CoV-2 mouse adapted 1 (SARS-CoV-2

Language: Английский

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Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

动物学研究, Journal Year: 2024, Volume and Issue: 45(4), P. 747 - 766

Published: Jan. 1, 2024

The distribution of the immune system throughout body complicates

Language: Английский

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Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

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

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Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 24, 2022

Abstract Background Ronapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and the treatment of seronegative patients with severe COVID19 prior to emergence Omicron variant late 2021. Numerous reports have described loss vitro neutralisation activity other monoclonal antibodies for BA.1 subsequent sub-lineages variant. With some exceptions, global policy makers recommended against use existing COVID19. Gaps knowledge regarding mechanism action are noted, further preclinical study will help understand positioning new under development. Objectives The purpose this was investigate impact on compartmental viral replication as a paradigm antibody combination. also sought confirm absence vivo (B.1.1.529) relative Delta (B.1.617.2) Methods Virological efficacy assessed K18-hACE2 mice inoculated either SARS-CoV-2 or variants. Viral tissues quantified using qRT-PCR measure sub-genomic RNA E gene (sgE) proxy. A histological examination combination staining antigen served determine spread associated damage. Results reduced levels lung nasal turbinate, 4 6 days post infection, but not at doses 2-fold higher than those shown be active previous variants virus. It appeared block brain infection which is seen high frequency after infection. At day 6, inflammatory response altered mild multifocal granulomatous inflammation virus confined. similar tendency observed infected, Ronapreve-treated animals. Conclusions current provides evidence an tissue that retains neutralization activity. These data demonstrate experimental designs reflect case achievable animal models deployed susceptible Extreme caution should taken when interpreting prophylactic assessing plausibility cases.

Language: Английский

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Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(8)

Published: July 16, 2024

ABSTRACT With some exceptions, global policymakers have recommended against the use of existing monoclonal antibodies in COVID-19 due to loss neutralization newer variants. The purpose this study was investigate impact Ronapreve on compartmental viral replication using paradigms for susceptible and insusceptible Virological efficacy pathogenicity assessed K18-hACE2 mice inoculated with either Delta or BA.1 Omicron reduced sub-genomic RNA levels lung nasal turbinate, 4 6 days post-infection, variant but not variant. It also blocked brain infection, which is seen high frequency after infection. At day 6, inflammatory response infection altered a multifocal granulomatous inflammation virus appeared be confined. current provides evidence an tissue SARS-CoV-2 treatment antibody combination that retains activity. These data demonstrate experimental designs reflect cases are achievable animal models antibodies. Extreme caution should taken when interpreting prophylactic may representative treatment. IMPORTANCE Following emergence variant, WHO its guidelines lack based pharmacokinetic-pharmacodynamic understanding. However, continued Ronapreve, specifically vulnerable patients, advocated by vitro data. Here, virological demonstrated both compartments as paradigm Conversely, Comparable concentrations were observed plasma Delta- Omicron-infected mice. This made reliable murine model design reflective treatment, utility approach assessing effectiveness

Language: Английский

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TMEM106B-mediated SARS-CoV-2 infection allows for robust ACE2-independent infection in vitro but not in vivo

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

Published: May 8, 2024

ABSTRACT Angiotensin converting enzyme 2 (ACE2) serves as the primary entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV-2). However, ACE2-independent has been observed in vitro SARS-CoV-2 strains containing E484D amino acid substitution spike protein. In this study, we conducted a whole genome CRISPR-Cas9 knockout screen using strain spike-E484D (SARS-CoV-2 MA1 ) to identify mechanisms. Our findings revealed that infection HEK293T cells relied on heparan sulfate and endocytic pathways, with TMEM106B emerging most significant contributor. While productively infected human brain organoids K18-hACE2 mouse brains, it did not infect C57BL/6J or Ifnar -/- brains. This suggests via TMEM106B, which is protein predominantly expressed brain, overtly increase risk of neuroinvasiveness wild-type mice. Importantly, replicate Ace2 tracts. Overall, robust by likely phenomenon specific conditions, no apparent clinical implications.

Language: Английский

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The effects of iron deficient and high iron diets on SARS-CoV-2 lung infection and disease

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

Published: Sept. 4, 2024

The severity of Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often dictated a range comorbidities. A considerable literature suggests iron deficiency and overload may contribute to increased infection, inflammation severity, although direct causal relationships have been difficult establish.

Language: Английский

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Increased neurovirulence of omicron BA.5 over BA.1 in human brain organoids and K18-hACE2 mice

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: March 31, 2023

Abstract 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 remains controversial. We show that a isolate was significantly more pathogenic in K18-hACE2 mice than isolate, with infections showing increased neuroinvasiveness, resulting brain infection and mortality, similar seen original ancestral isolates. also infected human cortical organoids greater extent In brains neurons were main target infection, neuronal progenitor cells immature infected. Evidence damage certain COVID-19 patients becoming compelling, results herein illustrating increasing intrinsic neuropathogenic potential evolving variants.

Language: Английский

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