Publications by authors named "Vineet Menachery"

Enhanced expression of Pellino-1 (Peli1), a ubiquitin ligase is known to be associated with COVID-19 susceptibility. The underlying mechanisms are not known. Here, we report that mice deficient in Peli1 (Peli1) had reduced viral load and attenuated inflammatory immune responses and tissue damage in the lung following SARS-CoV-2 infection.

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SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. Here we show that the host E3-ubiquitin ligase TRIM7 acts as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein.

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Coronaviruses (CoVs) maintain large RNA genomes that frequently undergoes mutations and recombination, contributing to their evolution and emergence. In this study, we find that SARS-CoV-2 has greater RNA recombination frequency than other human CoVs. In addition, coronavirus RNA recombination primarily occurs at uridine (U)-enriched RNA sequences.

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Over the past 25 years, the global community has faced challenges posed by three distinct outbreaks of coronaviruses including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The identification of a novel alphacoronavirus canine CoV (CCoV-HuPn2018) in human patients in Malaysia underscores the potential for crossover infections to humans. The threat of the ever-evolving nature of viral infections as well as the lingering health and socioeconomic effects of the recent SARS-CoV-2 pandemic emphasize the urgent need for advanced antiviral drug screening tools that can be quickly implemented to strengthen preparedness and preventive measures against future outbreaks.

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Waning immunity and the emergence of immune evasive SARS-CoV-2 variants jeopardize vaccine efficacy leading to breakthrough infections. We have previously shown that innate immune cells play a critical role in controlling SARS-CoV-2. To investigate the innate immune response during breakthrough infections, we modeled breakthrough infections by challenging low-dose vaccinated mice with a vaccine-mismatched SARS-CoV-2 Beta variant.

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SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein.

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Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses.

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Article Synopsis
  • - The study focuses on how mutations in SARS-CoV-2 variants, particularly the Delta variant, can help us understand both the virus's biology and the public health impact of these changes.
  • - Researchers identified a specific mutation (G215C) in the nucleocapsid (N) protein that creates a disulfide bond, leading to more stable protein structures (dimers) which enhance viral growth.
  • - The G215C mutation also results in the production of larger virions that contain more nucleocapsid proteins, indicating a potential impact on how the virus spreads.
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  • Coronavirus can lead to serious health issues, exemplified by SARS-CoV, MERS-CoV, and SARS-CoV-2 outbreaks, indicating significant variation in disease outcomes among infected individuals.
  • Researchers are using mouse models and human genetic studies to identify gene locations that influence how these coronaviruses affect infection severity and replication.
  • Their findings highlight specific genes that may play roles in virus response, offering insights for future research on how to combat similar viruses that jump from animals to humans.
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  • G3BP1 and G3BP2 are proteins that help form stress granules in cells during stress, like viral infections, but SARS-CoV-2's nucleocapsid (N) protein stops this process.
  • The study identifies a specific mutation (N-F17A) in the N protein that prevents its interaction with G3BP1/2, leading to an inability to inhibit stress granule formation.
  • This disruption results in lower viral replication and reduced illness in experimental models, showing that the G3BP1-N interaction is crucial for SARS-CoV-2’s ability to replicate and cause disease.
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  • SARS-CoV-2 interacts with host proteins to enhance viral replication and evade immune responses, with a focus on its NSP3 protein.
  • Researchers discovered that NSP3 binds to fragile X mental retardation proteins (FMRPs), and mutations preventing this binding lead to reduced virus replication and lower viral levels in lungs.
  • The study highlights how NSP3 disrupts the normal function of FMRPs by competing with another protein, shedding light on both viral mechanisms and potential links to fragile X syndrome.
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Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1 and FXR1-2).

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Coronaviruses (CoVs) have been the source of multiple epidemics and a global pandemic since the start of century, and there is an urgent need to understand CoV biology and develop better therapeutics. Here, we review the role of NSP16 in CoV replication, specifically its importance to 2'-O-methylation and CoV RNA capping. We describe the attenuation phenotypes of NSP16-mutant CoVs, the roles of MDA5 and IFITs in sensing and antagonizing viral RNA lacking 2'O methylation, and the dependence on 2'-O-methylation in other virus families.

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Article Synopsis
  • G3BP1 and G3BP2 are proteins that help form stress granules when cells face stress, like during a virus attack.
  • The study investigates how G3BP1 interacts with the nucleocapsid (N) protein of SARS-CoV-2 and what happens when this interaction is disrupted.
  • A mutation in the N protein (F17) impairs its ability to interact with G3BP1, leading to reduced viral replication and disease severity, implying that this interaction helps the virus evade the cellular stress response.
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RSV and SARS-CoV-2 are prone to co-infection with other respiratory viruses. In this study, we use RSV/SARS-CoV-2 co-infection to evaluate changes to clinical disease and viral replication in vivo. To consider the severity of RSV infection, effect of sequential infection, and the impact of infection timing, mice were co-infected with varying doses and timing.

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Article Synopsis
  • SARS-CoV-2 Omicron variants show over 30 new amino acid mutations, particularly in the spike protein, with three specific mutations in a less-studied region (CTS1) being the focus of this research.
  • The study created a triple mutant (YKH) that increased spike protein processing and a single N679K mutant, which resulted in lower viral replication and less disease severity.
  • Despite being a loss-of-function mutation, N679K showed enhanced replication in the upper airway compared to wild-type virus in hamsters, suggesting it may affect the virus's transmissibility.
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Several viruses have been shown to modulate the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the master regulator of redox homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, also seems to disrupt the balance between oxidants and antioxidants, which likely contributes to lung damage. Using and models of infection, we investigated how SARS-CoV-2 modulates the transcription factor NRF2 and its dependent genes, as well as the role of NRF2 during SARS-CoV-2 infection.

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The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro.

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Understanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein 16 (NSP16) of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2'--methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process.

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Unlabelled: Understanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein 16 (NSP16) of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2'- methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process.

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The Delta variant of SARS-CoV-2 has caused many breakthrough infections in fully vaccinated individuals. While vaccine status did not generally impact the number of viral RNA genome copies in nasopharyngeal swabs of breakthrough patients, as measured by Ct values, it has been previously found to decrease the infectious viral load in symptomatic patients. We quantified the viral RNA, infectious virus, and anti-spike IgA in nasopharyngeal swabs collected from individuals asymptomatically infected with the Delta variant of SARS-CoV-2.

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One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD).

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We report a live-attenuated SARS-CoV-2 vaccine candidate with (i) re-engineered viral transcription regulator sequences and (ii) deleted open-reading-frames (ORF) 3, 6, 7, and 8 (∆3678). The ∆3678 virus replicates about 7,500-fold lower than wild-type SARS-CoV-2 on primary human airway cultures, but restores its replication on interferon-deficient Vero-E6 cells that are approved for vaccine production. The ∆3678 virus is highly attenuated in both hamster and K18-hACE2 mouse models.

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The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates.

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