Mohsan Saeed

Mitochondrial OXPHOS restricts SARS-CoV-2 replication

Yentli E. Soto Albrecht, Ryan M. Morrow, Devin Kenney, Arnold Z. Olali et autres

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rewires host metabolism to optimize virus production. Although glycolysis is necessary for virus production, the importance of mitochondrial oxidative phosphorylation (OXPHOS) is unknown. The mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS polypeptides plus the …

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eIF4E3 drives translation of viral mRNAs with short 5’UTRs

Autumn O Grimins, Mollie A. Brekker, Sarah Ruth Shick, Ellen L. Suder et autres

ABSTRACT Eukaryotic cells express three paralogs of the cap-binding protein eIF4E, yet the functions of the less-studied family members remain poorly understood. Here we demonstrate that eIF4E3, a paralog whose expression is tissue-restricted and whose activity is insensitive to inhibition by eIF4E-binding …

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The enteroviral protease target LSM14A operates outside of P-bodies to augment antiviral innate immunity

Alan Wacquiez, Hicham Hboub, Da‐Yuan Chen, Alexander H. Tavares et autres

Antiviral innate immune networks in human cells comprise core components that serve as central signaling hubs and several context-dependent modulators whose role may be virus- or tissue-specific. One such modulator is LSM14A, which potentiates innate immune response but is not essential. We …

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Proteolytic dissection of eIF4G reveals the closed-loop mRNP as an architecture for translation repression

Ryan A. Johnston, Mollie A. Brekker, Noelle Khalil, Monty E. Goldstein et autres

Abstract Formation of a “closed-loop” mRNP, in which the 5′ cap and 3′ poly(A) tail are bridged by eIF4E-eIF4G-PABP interactions, has long been proposed to drive efficient translation initiation. Direct tests of this model in mammalian cells have remained elusive. Using auxin-inducible …

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Structure-Guided Design of Potent and Selective Covalent Inhibitors Targeting the SARS-CoV-2 Papain-like Protease

Mona Sharafi, Wei Pin Teh, Jeremy B. A. Green, Paul S. Charifson et autres

The COVID-19 pandemic led to numerous initiatives to create antiviral medications and vaccines for the treatment and prevention of infections. However, the need remains for new therapies with distinct mechanisms of action from current treatment of COVID-19 infections as well as for …

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Genetic and chemical correction of cystic fibrosis reduces airway susceptibility to SARS-CoV-2

S. Rollins, A. Hume, D. W. Chen, Rebecca Yeboah et autres

Using rigorously controlled iPSC-derived airway models, the study shows that CFTR-deficient cells are more vulnerable to SARS-CoV-2 and display stronger inflammation than syngeneic CFTR-corrected controls. The CFTR modulator ETI reduces viral injury and boosts antiviral pathways in both CF and non-CF cells. …

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Structural Definition of Neutralizing Epitopes within and around the HKU1 Receptor-binding Site Reveals Cell Context–Dependent Neutralization

Jeswin Joseph, Lingshu Wang, Sheena Vasquez, Chia-Ming Su et autres

Abstract Endemic human coronaviruses (HCoVs), such as HCoV-HKU1, account for ∼30% of common colds each year and can cause serious upper and lower respiratory infections, yet no licensed vaccines or therapeutic antibodies target HCoVs. Despite being endemic to the human population, little …

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A scalable proteogenomic framework for dissecting phospho-signaling pathways in primary immune cells

Christian Michel Beusch, Carolyn Morningstar, Marc Semaan, Christopher M. Monaco et autres

Abstract Signaling networks modulated by post-translational modifications orchestrate cellular responses to external cues. Traditional approaches to study these pathways lack the throughput to systematically capture the causal architecture of these signaling pathways at scale. Here, we present an integrated proteogenomic framework that …

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Comprehensive Analysis of the Impact of Weight Loss Thresholds on Mouse Models of Fatal Viral Infection

Devin Kenney, Giulia Unali, Alan Wacquiez, Mohsan Saeed et autres

Preclinical studies in virological research are pivotal to comprehend mechanisms of viral virulence and pathogenesis and evaluate antiviral therapies or vaccines. Mouse models, through access to various genetic strains and amenable reagents, along with their ease of implementation and cost-effectiveness, remain the …

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SARS-CoV-2 nsp15 enhances viral virulence by subverting host antiviral defenses

Allen Caobi, Chia-Ming Su, Christian Michel Beusch, Devin Kenney et autres

SARS-CoV-2 encodes numerous virulence factors, yet their precise mechanisms of action remain unknown. We provide evidence that the SARS-CoV-2 nonstructural protein 15 (nsp15) enhances viral virulence by suppressing the production of viral double-stranded (dsRNA), a potent inducer of antiviral signaling. The viral …

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Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways

Monika Evdokimova, Shuchen Feng, Allen Caobi, Fernando R. Moreira et autres

Identifying conserved mechanisms used by viruses to delay host innate responses can reveal potential targets for antiviral therapeutics. Here, we investigated coronavirus nonstructural protein 15 (nsp15), which encodes a highly conserved endoribonuclease (EndoU). EndoU functions as an immune antagonist by limiting the …

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Amidino-rocaglates (ADRs), a class of synthetic rocaglates, are potent inhibitors of SARS-CoV-2 replication through inhibition of viral protein synthesis

Patrick T. Keiser, Wenhan Zhang, Michael Ricca, Alan Wacquiez et autres

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