SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 28(7), P. 2878 - 2893

Published: Nov. 1, 2022

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases probable Parkinson's disease. As microglial NLRP3 inflammasome activation major driver neurodegeneration, here we interrogated whether promote activation. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as COVID-19 pre-clinical model, established the presence virus in brain together with and upregulation comparison to uninfected mice. Next, utilising model monocyte-derived microglia, identified isolates bind enter microglia absence viral replication. This interaction directly induced robust activation, even another priming signal. Mechanistically, demonstrated purified spike glycoprotein activated LPS-primed ACE2-dependent manner. Spike protein could prime through NF-κB signalling, allowing for either ATP, nigericin or α-synuclein. Notably, protein-mediated was significantly enhanced α-synuclein fibrils entirely ablated by NLRP3-inhibition. Finally, demonstrate infected hACE2 treated orally post-infection inhibitory drug MCC950, have reduced increased survival untreated These results support possible mechanism innate immune SARS-CoV-2, which explain vulnerability developing symptoms akin disease individuals, potential therapeutic avenue intervention.

Language: Английский

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In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants

Acta Neuropathologica Communications, Journal Year: 2022, Volume and Issue: 10(1)

Published: Sept. 4, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism not fully understood, several studies have shown that neuroinflammation occurs in and post-acute phase. As these predominantly been performed isolates from 2020, it unknown if there are differences among SARS-CoV-2 variants their ability to cause neuroinflammation. Here, we compared neuroinvasiveness, neurotropism neurovirulence of ancestral strain D614G, Delta (B.1.617.2) Omicron BA.1 (B.1.1.529) using vitro vivo models. The variant showed reduced D614G human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured astrocytes. Similar were obtained Syrian hamsters inoculated 5 days post infection. Replication olfactory mucosa was observed all hamsters, but most prominently hamsters. Furthermore, neuroinvasion into CNS via nerve or bulb D614G. Altogether, our findings suggest neuroinvasive, neurotropic neurovirulent potential between hiPSC-derived neural cultures during phase

Language: Английский

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The neurobiology of SARS-CoV-2 infection

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 25(1), P. 30 - 42

Published: Dec. 4, 2023

Language: Английский

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Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(2), P. 226 - 238

Published: Jan. 9, 2023

Language: Английский

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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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Delayed tumor-draining lymph node irradiation preserves the efficacy of combined radiotherapy and immune checkpoint blockade in models of metastatic disease

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 29, 2024

Abstract Cancer resistance to immune checkpoint inhibitors motivated investigations into leveraging the immunostimulatory properties of radiotherapy overcome evasion and improve treatment response. However, clinical benefits radiotherapy-immunotherapy combinations have been modest. Routine concomitant tumor-draining lymph node irradiation (DLN IR) might be culprit. As crucial sites for generating anti-tumor immunity, DLNs are indispensable in situ vaccination effect radiotherapy. Simultaneously, DLN sparing is often not feasible due metastatic spread. Using murine models disease female mice, here we demonstrate that delayed (adjuvant), but neoadjuvant, IR overcomes detrimental on efficacy radio-immunotherapy. Moreover, identify IR-induced disruption CCR7-CCL19/CCL21 homing axis as a key mechanism IR. Our study proposes strategy maximize radio-immunotherapy across different tumor types stages.

Language: Английский

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Sequential Infection with Influenza A Virus Followed by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Leads to More Severe Disease and Encephalitis in a Mouse Model of COVID-19

Viruses, Journal Year: 2024, Volume and Issue: 16(6), P. 863 - 863

Published: May 28, 2024

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2. The coalescence SARS-CoV-2 seasonal respiratory viruses, particularly influenza global health concern. To understand this, transgenic mice expressing the human ACE2 receptor (K18-hACE2) were infected A virus (IAV) followed and host response effect on biology was compared to K18-hACE2 IAV or alone. sequentially showed reduced RNA synthesis, yet exhibited more rapid weight loss, severe lung damage prolongation innate singly control mice. Sequential also exacerbated extrapulmonary encephalitic manifestations associated infection. Conversely, prior commercially available, multivalent live-attenuated vaccine (Fluenz Tetra) elicited same reduction albeit without increase disease severity. This suggests that immune stimulated inhibits Interestingly, an attenuated, apathogenic does not result aberrant enhanced Taken together, data suggest coinfection (‘twinfection’) deleterious mitigation steps should be instituted as part comprehensive public management strategy COVID-19.

Language: Английский

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Ancestral allele of DNA polymerase gamma modifies antiviral tolerance

Nature, Journal Year: 2024, Volume and Issue: 628(8009), P. 844 - 853

Published: April 3, 2024

Abstract Mitochondria are critical modulators of antiviral tolerance through the release mitochondrial RNA and DNA (mtDNA mtRNA) fragments into cytoplasm after infection, activating virus sensors type-I interferon (IFN-I) response 1–4 . The relevance these mechanisms for diseases remains understudied. Here we investigated recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in polymerase gamma ( POLG1 ) 5 Patients homozygous MIRAS variant p.W748S show exceptionally variable ages onset symptoms , indicating that unknown modifying factors contribute to disease manifestation. We report mtDNA replicase has role defence double-stranded positive-strand infections (HSV-1, TBEV SARS-CoV-2), its dampens innate immune responses. Our patient knock-in mouse data compromises replisome stability, causing depletion, aggravated infection. Low mtRNA slow IFN offer viruses an early replicative advantage, leading augmented pro-inflammatory response, subacute loss GABAergic neurons liver inflammation necrosis. A population databank around 300,000 Finnish individuals 6 demonstrates enrichment immunodeficient traits carriers mutation. evidence suggests defects compromise tolerance, triggering epilepsy disease. finding important implications spectrum, including epilepsy, parkinsonism.

Language: Английский

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SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

PLoS ONE, Journal Year: 2022, Volume and Issue: 17(8), P. e0273430 - e0273430

Published: Aug. 29, 2022

The COVID-19 pandemic has been fueled by SARS-CoV-2 novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties enhance disease. goal this study is to characterize unique pathogenesis the Delta VOC strain in K18-hACE2-mouse challenge model. Challenge studies suggested lethal dose was higher than Alpha or Beta strains. To differences strain's pathogenesis, a time-course experiment performed evaluate overall host response variant challenge. qRT-PCR analysis Alpha- Delta-challenged mice revealed no significant difference between viral RNA burden lung, nasal wash brain. However, histopathological high lung tissue inflammation cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest 6 suggesting enhanced pneumonia. Total RNA-sequencing lungs comparing challenged Alpha-challenged more total genes differentially activated. Conversely, magnitude differential gene expression. interferon-dependent expression IFN-γ production compared Alpha. Analysis TCR clonotypes T-cell challenged. Our data suggest evolved engage interferon responses manner may pathogenesis. vivo silico observations underscore need conduct experiments with strains best model when evaluating therapeutics vaccines.

Language: Английский

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The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 4(1), P. 100893 - 100893

Published: Dec. 29, 2022

COVID-19 convalescent plasmas (CCPs) are chosen for plasma therapy based on neutralizing titers and anti-Spike immunoglobulin levels. However, CCP characteristics that promote SARS-CoV-2 control complex incompletely defined. Using an in vivo imaging approach, we demonstrate CCPs with low (ID50 ≤ 1:250), but moderate to high Fc-effector activity, contrast those poor Fc function, delay mortality and/or improve survival of SARS-CoV-2-challenged K18-hACE2 mice. The impact innate immune cells efficacy depended their residual activity. Fractionation a selected revealed IgG Ig(M + A) were required during therapy, the fraction alone sufficed prophylaxis. Finally, despite reduced neutralization, ancestral SARS-CoV-2-elicited significantly delayed Delta Beta-induced suggesting functions contribute immunity against VOCs. Thus, activity provide second line defense when neutralization is compromised can serve as important criterion selection.

Language: Английский

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