SARS-CoV-2 and innate immunity: the good, the bad, and the “goldilocks”

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 21(2), P. 171 - 183

Published: Nov. 20, 2023

Abstract An ancient conflict between hosts and pathogens has driven the innate adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that be leveraged therapeutically. The humoral response to SARS-CoV-2 infection been focus intense research, role immune system received significantly less attention. Here, we review current knowledge various means employs evade defense systems. We consider immunity in vaccines phenomenon long COVID.

Language: Английский

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SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(35)

Published: Aug. 22, 2023

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies COVID-19. Included in these drug is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein a small domain at N terminus of nonstructural 3. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical both murine hepatitis virus (MHV) severe acute respiratory syndrome (SARS)-CoV virulence. However, potential target, it imperative understand how complete deletion impacts replication pathogenesis different CoVs. To this end, we created bacterial artificial chromosomes (BACs) containing deletions (ΔMac1) MHV, MERS-CoV, SARS-CoV-2. While were unable recover infectious from MHV MERS-CoV ΔMac1 BACs, SARS-CoV-2 readily recovered BAC transfection, indicating stark difference requirement between Furthermore, replicated near wild-type levels multiple cell lines susceptible infection. mouse model infection, quickly cleared causing minimal pathology without any morbidity. induced increased interferon (IFN) IFN-stimulated gene expression culture mice, that blocks IFN responses which may contribute its attenuation. infection also led reduction inflammatory monocytes neutrophils. These results demonstrate only minimally replication, unlike but required unique target.

Language: Английский

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Membrane remodeling and trafficking piloted by SARS-CoV-2

Trends in Cell Biology, Journal Year: 2024, Volume and Issue: 34(9), P. 785 - 800

Published: Jan. 22, 2024

The molecular mechanisms underlying SARS-CoV-2 host cell invasion and life cycle have been studied extensively in recent years, with a primary focus on viral entry internalization the aim of identifying antiviral therapies. By contrast, our understanding involved later steps coronavirus is relatively limited. In this review, we describe what known about factors proteins replication, assembly, egress phases SARS-CoV-2, which induce significant membrane rearrangements. We also discuss limits current approaches knowledge gaps still to be addressed.

Language: Английский

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SARS-CoV-2 variant of concern fitness and adaptation in primary human airway epithelia

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114076 - 114076

Published: April 1, 2024

The severe acute respiratory syndrome coronavirus 2 pandemic is characterized by the emergence of novel variants concern (VOCs) that replace ancestral strains. Here, we dissect complex selective pressures evaluating variant fitness and adaptation in human tissues. We evaluate viral properties host responses to reconstruct forces behind D614G through Omicron (BA.1) emergence. observe differential replication airway epithelia, differences cellular tropism, virus-induced cytotoxicity. accumulates most mutations after infection, supporting zoonosis airway. perform head-to-head competitions highest for Gamma Delta. Under these conditions, RNA recombination favors encoding B.1.617.1 lineage 3' end. Based on growth kinetics, Alpha, Gamma, Delta exhibit increased compared D614G. In contrast, global success likely derives from transmission antigenic variation. Our data provide molecular evidence support epidemiological observations VOC

Language: Английский

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Mutation of a highly conserved isoleucine residue in loop 2 of several 𝛽-coronavirus macrodomains indicates that enhanced ADP-ribose binding is detrimental to infection

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

Published: Jan. 4, 2024

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown important virus replication pathogenesis. Within Mac1, there are several regions highly across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how biochemical activities of these residues impact CoV replication, isoleucine phenylalanine were mutated to alanine (I-A/F-A) both recombinant proteins murine hepatitis (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute 2 (SARS-CoV-2). The F-A mutant had ADP-ribose binding and/or hydrolysis defects led attenuated pathogenesis cell culture mice. In contrast, I-A mutations normal enzyme activity enhanced binding. Despite increased binding, MERS-CoV SARS-CoV-2 mice, indicating this residue acts as gate controls efficient replication. These results highlight function provide unique insight into macrodomains control promote viral

Language: Английский

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The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

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

Published: Aug. 9, 2024

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication

Language: Английский

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IFN-γ signaling is required for the efficient replication of murine hepatitis virus (MHV) strain JHM in the brains of infected mice.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

ABSTRACT Neurotropic viruses are a major public health concern as they can cause encephalitis and other severe brain diseases. Many of these viruses, including flaviviruses, herpesviruses, rhabdoviruses alphaviruses enter the through olfactory neuroepithelium (ONE) in bulbs (OB). Due to low percentage that occurs following infections, it’s thought OBs have specialized innate immune responses eliminate viruses. Murine hepatitis virus strain JHM (JHMV) is model coronavirus causes mice access sensory neurons. We’ve shown JHMV Mac1-mutant virus, N1347A, has decreased replication disease brains mice. Here we further show this replicates poorly OB. However, it unknown which factors restrict N1347A RNA seq analysis infected showed IFNγ was upregulated OB while IFN- β barely detectable at 5 days post-infection. To determine if IFN-γ restricts replication, utilized receptor (IFN-γR) knockout (KO) Surprisingly found WT replicated very whole both IFN-γR KO intranasal infection, though survival weight loss were unaltered. Furthermore, determined microglia primary cells producing during early stages infection. We conclude required for efficient

Language: Английский

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The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

Published: Jan. 6, 2025

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

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The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2

Published: Jan. 6, 2025

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

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Torsional twist of the SARS‐CoV and SARS‐CoV‐2 SUD‐N and SUD‐M domains

Protein Science, Journal Year: 2025, Volume and Issue: 34(3)

Published: Feb. 19, 2025

Abstract Coronavirus non‐structural protein 3 (nsp3) forms hexameric crowns of pores in the double membrane vesicle that houses replication–transcription complex. Nsp3 SARS‐like viruses has three unique domains absent other coronavirus nsp3 proteins. Two these, SUD‐N (Macrodomain 2) and SUD‐M 3), form two lobes connected by a peptide linker an interdomain disulfide bridge. We resolve first complete x‐ray structure SARS‐CoV SUD‐N/M as well mutant variant SARS‐CoV‐2 modified to restore cysteines for bond naturally lost evolution. Comparative analysis all structures revealed are not rigidly associated but rather have significant rotational flexibility. Phylogenetic supports potential is common across betacoronavirus isolates from many bat species civets, also one or both bats pangolins. The absence these does impact viral replication translation.

Language: Английский

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