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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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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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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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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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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Neurovirulence of the Australian outbreak Japanese Encephalitis virus genotype 4 is lower compared to genotypes 2 and 3 in mice and human cortical brain organoids

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

Published: April 27, 2023

SUMMARY Background Human infections with 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. Methods Herein we compared the neuropathology , FU (genotype 2) and Nakayama 3) adult C57BL/6J wild-type mice, mice deficient interferon regulatory factor 7 ( Irf7 -/- ), type I receptor Ifnar as well human cortical brain organoids (hBOs). Using serum post-Imojev vaccination, performed neutralisation assays to determine susceptibility vaccine responses. Findings In lethal outcomes, infection histopathological lesions recapitulated those seen humans primates. universally by day 3 histological signs hemorrhage, but produced no other detectable or lesions, protein detected blood vessels not neurons. We thus describe new mouse model for which had increased viremia allowing neuroinvasive one mouse. Overall, less neurovirulent than isolates more sensitive interferon. All showed robust cytopathic organoids, albeit lower . also show that Imojev vaccination induced neutralizing antibodies against level cross-neutralisation related conservation envelope amino acid sequences each isolate. Interpretation Our study establishes models infection, possible rarer genotypes. regimens may afford protection this newly emerged strain, although antibody responses sub-optimal. Funding QIMRB received generous philanthropic donation Brazil Family Foundation awarded D.J.R. support Encephalitis research at QIMRB. A.S. holds Investigator grant National Health Medical Research Council (NHMRC) Australia (APP1173880). acknowledge intramural QIMR Berghofer R.S. purchase CelVivo Clinostar incubator producing organoids. The project “Japanese via intradermal route children adults (JEVID-2): A clinical trial comparing immunogenicity safety administered subcutaneous routes” being conducted G.D., N.G., N.W. funded Sydney Children’s Hospitals Network New South Wales Health. context Evidence before historically rare causing outbreak, 44 cases fatalities. While range have been reported, none them infect efficacy current vaccines unclear. Added value establish characterised subcutaneously infected recapitulate many aspects disease including severe lesions. Prolonged significantly associated neuroinvasiveness mice. demonstrate Australian isolate, exhibited markedly diminished neuroinvasion recipients, were present, sub-optimal titers. Implications all available evidence establishment neuropenetrance after peripheral inoculation is important tool can now be deployed pre-clinical studies understand pathogenesis. suggests should developed circulating strains optimal

Language: Английский

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Harnessing defective interfering particles and lipid nanoparticles for effective delivery of an anti-dengue virus RNA therapy

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

Published: April 23, 2024

Abstract Presently, no approved antiviral drug targets dengue virus (DENV) infection. Treatment mainly relies on supportive measures, while DENV vaccines’ efficacy varies based factors like vaccine type, circulating serotypes and vaccinated population. This study explores using defective interfering particles (DIPs) lipid nanoparticles (LNPs) to deliver an anti-DENV RNA, known as DI290. Results showed that both DIPs DI290 loaded LNPs (LNP-290) effectively suppressed infection in human primary monocyte-derived macrophages (MDMs), THP-1 fibroblasts, representing cell types naturally targeted by DENV. Furthermore, LNP-290 demonstrated >log 10 inhibition of viral loads IFNAR-deficient mice, which lack functional type I interferon (IFN) receptors. DI290-mediated was also effective IFN regulatory factor 3 7 double knockout mice. RNA-Seq data from LNP-treated C57BL/6J mice MDMs treated with or illustrated treatment heightened responses, particularly IFNγ, well IFNα/β IFNλ. thus induces a broad range IFNγ IFNλ providing anti-viral activity when responses are absent. Mice administered did not manifest acute overt clinical signs. In summary, these experiments suggest DI290’s potential therapeutic approach for combating

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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