Fc-γR-dependent antibody effector functions are required for vaccine-mediated protection against antigen-shifted variants of SARS-CoV-2

Nature Microbiology, Journal Year: 2023, Volume and Issue: 8(4), P. 569 - 580

Published: April 3, 2023

Language: Английский

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Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Cell Host & Microbe, Journal Year: 2023, Volume and Issue: 31(10), P. 1668 - 1684.e12

Published: Sept. 21, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, roles and contributions of during physiological infection remain unexplored. We assessed role using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. plays key antagonism viral pathogenesis interfering import specifically translocation IRF STAT transcription factors. Additionally, inhibits cellular mRNA export, resulting remodeling cell proteome, regulates protein expression. Interestingly, ORF6:D61L emerged Omicron BA.2 BA.4 variants exhibits reduced Nup98-Rae1 consequently impairs immune evasion. Our findings highlight antagonizing innate immunity emphasize importance studying evasion strategies SARS-CoV-2.

Language: Английский

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Fibrin drives thromboinflammation and neuropathology in COVID-19

Nature, Journal Year: 2024, Volume and Issue: 633(8031), P. 905 - 913

Published: Aug. 28, 2024

Abstract Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 persistent patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection 1–4 . Despite the clinical evidence 1,5–7 , underlying mechanisms coagulopathy its consequences inflammation neuropathology remain poorly understood treatment options insufficient. Fibrinogen, central structural component blood clots, is abundantly deposited lungs brains COVID-19, correlates disease severity a predictive biomarker for post-COVID-19 cognitive deficits 1,5,8–10 Here we show that fibrin binds to spike protein, forming proinflammatory clots drive systemic thromboinflammation COVID-19. Fibrin, acting through inflammatory domain, required oxidative stress macrophage activation lungs, whereas it suppresses natural killer cells, after infection. Fibrin promotes neuroinflammation neuronal loss infection, as well innate immune brain independently active A monoclonal antibody targeting domain provides protection from microglial injury, lung Thus, drives fibrin-targeting immunotherapy may represent therapeutic intervention acute COVID.

Language: Английский

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COVID-19 drug discovery and treatment options

Nature Reviews Microbiology, Journal Year: 2024, Volume and Issue: 22(7), P. 391 - 407

Published: April 15, 2024

Language: Английский

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Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue

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

Published: Jan. 30, 2024

Omicron emerged following COVID-19 vaccination campaigns, displaced previous SARS-CoV-2 variants of concern worldwide, and gave rise to lineages that continue spread. Here, we show exhibits increased infectivity in primary adult upper airway tissue relative Delta. Using recombinant forms nasal epithelial cells cultured at the liquid-air interface, mutations unique Spike enable enhanced entry into tissue. Unlike earlier SARS-CoV-2, our findings suggest enters independently serine transmembrane proteases instead relies upon metalloproteinases catalyze membrane fusion. Furthermore, demonstrate this pathway unlocked by enables evasion from constitutive interferon-induced antiviral factors restrict attachment. Therefore, transmissibility exhibited humans may be attributed not only its vaccine-elicited adaptive immunity, but also superior invasion epithelia resistance cell-intrinsic barriers present therein.

Language: Английский

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An intranasal ASO therapeutic targeting SARS-CoV-2

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 3, 2022

Abstract The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and may partially evade vaccine antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable preventing infection by all could complement current vaccination efforts help turn the tide on pandemic. Here, we describe a novel strategy targeting RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identify LNA ASO binding to 5′ leader sequence disrupts highly conserved stem-loop structure nanomolar efficacy in viral replication human cells. Daily intranasal administration this mouse model potently suppresses (>80-fold) lungs infected mice. find efficacious countering “variants concern” tested both vitro vivo. Hence, inhaled ASOs represents promising approach reduce or prevent transmission decrease severity individuals. are chemically stable can be flexibly modified target different sequences stockpiled for future coronavirus pandemics.

Language: Английский

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Infection of primary nasal epithelial cells differentiates among lethal and seasonal human coronaviruses

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(15)

Published: April 6, 2023

The nasal epithelium is the initial entry portal and primary barrier to infection by all human coronaviruses (HCoVs). We utilize epithelial cells grown at air-liquid interface, which recapitulate heterogeneous cellular population as well mucociliary clearance functions of in vivo epithelium, compare lethal [Severe acute respiratory syndrome (SARS)-CoV-2 Middle East syndrome-CoV (MERS-CoV)] seasonal (HCoV-NL63 HCoV-229E) HCoVs. All four HCoVs replicate productively cultures, though replication differentially modulated temperature. Infections conducted 33 °C vs. 37 (reflective temperatures upper lower airway, respectively) revealed that both -229E) significantly attenuated °C. In contrast, SARS-CoV-2 MERS-CoV temperatures, enhanced late infection. These also diverge terms cytotoxicity induced following infection, cause disruption, while does not. Treatment cultures with type 2 cytokine IL-13 mimic asthmatic airways impacts HCoV receptor availability replication. DPP4 expression increases treatment, whereas ACE2, used HCoV-NL63, down-regulated. treatment enhances HCoV-229E but reduces reflecting impact on availability. This study highlights diversity among during likely influence downstream outcomes such disease severity transmissibility.

Language: Английский

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Bacterial-induced or passively administered interferon gamma conditions the lung for early control of SARS-CoV-2

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 12, 2023

Type-1 and type-3 interferons (IFNs) are important for control of viral replication; however, less is known about the role Type-2 IFN (IFNγ) in anti-viral immunity. We previously observed that lung infection with Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 mice yet drives low levels type-1 IFNs but robust IFNγ. Here we examine ongoing IFNγ responses to pre-established bacterial on disease outcomes two murine models. report required iv induced reduction pulmonary loads, an outcome dependent receptor expression by non-hematopoietic cells. Importantly, show prompts epithelial cells upregulate IFN-stimulated genes reported activity IFNγ-dependent manner, suggesting a possible mechanism protection. Finally, confirm properties demonstrating recombinant cytokine itself challenge when administered intranasally. Together, our data response within protective infection, concurrent or recent infections drive may limit pathogenesis supporting prophylactic uses COVID-19 management.

Language: Английский

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Innate immunity and interferon in SARS-CoV-2 infection outcome

Immunity, Journal Year: 2023, Volume and Issue: 56(7), P. 1443 - 1450

Published: July 1, 2023

Language: Английский

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Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses

JCI Insight, Journal Year: 2024, Volume and Issue: 9(9)

Published: April 4, 2024

The viral kinetics of documented SARS-CoV-2 infections exhibit a high degree inter-individual variability. We identified six distinct shedding patterns, which differed according to peak load, duration, expansion rate and clearance rate, by clustering data from 768 in the National Basketball Association cohort. Omicron variant previously vaccinated individuals generally led lower cumulative levels than other scenarios. then developed mechanistic mathematical model that recapitulated 1510 observed trajectories, including rebound cases reinfection. Lower loads were explained more rapid sustained transition susceptible cells refractory state during infection, as well an earlier potent late, cytolytic immune response. Our results suggest elimination occurs rapidly omicron following vaccination, re-infection due enhanced innate acquired responses. Because load has been linked with COVID-19 severity transmission risk, our provides framework for understanding wide range infection outcomes.

Language: Английский

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