Multi‐omic and comparative analyses revealed monocyte‐derived alpha‐defensin‐1 correlated with COVID‐19 severity and inhibited SARS‐CoV‐2 infection DOI
Xijing Qian,

Bingan Wu,

X. Chen

et al.

Journal of Medical Virology, Journal Year: 2023, Volume and Issue: 95(6)

Published: May 31, 2023

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the etiological pathogen of disease 2019 (COVID‐19), a highly contagious disease, spreading quickly and threatening global public health. The symptoms COVID‐19 vary from mild reactions to severe distress or even fatal outcomes probably due different status host immunity against virus. Here in study, we unveiled plasma proteomic signatures transcriptional patterns peripheral blood mononuclear cells (PBMCs) using samples 10 patients with severity. Through systemic analysis, α‐defensin‐1 (DEFA1) was identified be elevated both PBMCs, correlated severity stages. In vitro study demonstrated that DEFA1 secreted immunocytes suppressed SARS‐CoV‐2 infection original mutated strains dose dependency. By sequencing data, discovered activated monocytes through NF‐κB signaling pathway after infection, into circulation perturb by interfering protein kinase C expression. It worked mainly during virus replication instead entry cells. Together, anti‐SARS‐CoV‐2 mechanism has corner how innate explored its clinical potential prognosis therapeutic intervention.

Language: Английский

Viral persistence, reactivation, and mechanisms of long COVID DOI Creative Commons
Benjamin K. Chen,

Boris Jülg,

Sindhu Mohandas

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: May 4, 2023

The COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has infected hundreds of millions individuals. Following infection, a subset can develop wide range chronic symptoms affecting diverse organ systems referred to as post-acute sequelae SARS-CoV-2 (PASC), also known long COVID. A National Institutes Health-sponsored initiative, RECOVER: Researching COVID Enhance Recovery, sought understand basis in large cohort. Given that occur COVID, mechanisms may underlie these be diverse. In this review, we focus on emerging literature supporting role(s) viral persistence or reactivation viruses play PASC. Persistence RNA antigens is reported some organs, yet mechanism which they do so and how associated with pathogenic immune responses unclear. Understanding RNA, antigen other reactivated relate specific inflammatory drive PASC provide rationale for treatment.

Language: Английский

Citations

144
PANoptosis: Mechanisms, biology, and role in disease DOI Open Access

Xu Sun,

Yanpeng Yang,

Xiaona Meng

et al.

Immunological Reviews, Journal Year: 2023, Volume and Issue: 321(1), P. 246 - 262

Published: Oct. 12, 2023

Summary Cell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which mediated by multifaceted PANoptosome complexes assembled via integrating components from other modalities. There growing interest in process function of PANoptosis. Accumulating evidence suggests that occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, cancer. Given impact across disease spectrum, this review briefly describes relationships highlights key molecules formation activation, outlines roles diseases together with potential therapeutic targeting. We also discuss important concepts pressing issues future research. Improved understanding its mechanisms crucial identifying novel targets strategies.

Language: Английский

Citations

77
Mucosal and systemic immune correlates of viral control after SARS-CoV-2 infection challenge in seronegative adults DOI
Helen R. Wagstaffe, Ryan S. Thwaites, Arnold Reynaldi

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(92)

Published: Feb. 9, 2024

Human infection challenge permits in-depth, early, and pre-symptomatic characterization of the immune response, enabling identification factors that are important for viral clearance. Here, we performed intranasal inoculation 34 young adult, seronegative volunteers with a pre-Alpha severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Of these participants, 18 (53%) became infected showed an interferon-dominated mediator response divergent kinetics between nasal systemic sites. Peripheral CD4

Language: Английский

Citations

32
Interferon induction, evasion, and paradoxical roles during SARS‐CoV‐2 infection* DOI Creative Commons
Carolina Chiale, Trever T. Greene, Elina I. Zúñiga

et al.

Immunological Reviews, Journal Year: 2022, Volume and Issue: 309(1), P. 12 - 24

Published: July 1, 2022

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative agent of disease 2019 (COVID‐19), has caused millions deaths in past two years. Although initially little was understood about this virus, recent research significantly advanced and landed interferons (IFNs) spotlight. While Type I III IFN have long been known as central to antiviral immunity, case COVID‐19 their role controversial. However, protective function is now well supported by identification human deficiencies responses a predictor severity. Here, we will review cell types pathways that lead production importance timing location for outcome. We further discuss mechanisms SARS‐CoV‐2 uses evade responses, current efforts implement IFNs therapeutics treatment COVID‐19. It essential understand relationships between better inform treatments exploit functions alleviate

Language: Английский

Citations

47
The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands DOI Creative Commons
Wenshuai Wang, Anna Marie Pyle

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(21), P. 4131 - 4144.e6

Published: Oct. 21, 2022

RIG-I is an essential innate immune receptor for detecting and responding to infection by RNA viruses. specifically recognizes the unique molecular features of viral molecules selectively distinguishes them from closely related RNAs abundant in host cells. The physical basis this exquisite selectivity revealed through a series high-resolution cryo-EM structures complex with ligands. These studies demonstrate that actively samples double-stranded cytoplasm adopting two different types protein folds. Upon binding RNA, adopts high-affinity conformation conducive signaling, while induces autoinhibited stimulates release. By coupling folding selectivity, differ as little one phosphate group, thereby explaining selective antiviral sensing induction autoimmunity upon dysregulation.

Language: Английский

Citations

39
SARS-CoV-2 Mac1 is required for IFN antagonism and efficient virus replication in cell culture and in mice DOI Creative Commons
Yousef M. Alhammad,

Srivatsan Parthasarathy,

Roshan Ghimire

et al.

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

Citations

39
Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia DOI Creative Commons
Ana García‐García, Rebeca Pérez de Diego, Carlos Flores

et al.

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(5)

Published: March 3, 2023

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4–dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients autosomal MyD88 or IRAK-4 infected (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds eight countries on three continents. 16 were hospitalized: six moderate, four severe, critical pneumonia, one whom died. The risk increased age. invasive mechanical ventilation was also much greater than age-matched controls the general population (OR: 74.7, 95% CI: 26.8–207.8, P < 0.001). patients’ susceptibility can be attributed impaired TLR7-dependent by pDCs, which do not sense correctly. Patients inherited long thought selectively vulnerable pyogenic bacteria, but have pneumonia.

Language: Английский

Citations

35
SARS‐CoV‐2 NSP7 inhibits type I and III IFN production by targeting the RIG‐I/MDA5, TRIF, and STING signaling pathways DOI

Jian Deng,

Yi Zheng,

Shengnan Zheng

et al.

Journal of Medical Virology, Journal Year: 2023, Volume and Issue: 95(3)

Published: Feb. 9, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited production type I III interferons (IFNs) by targeting RIG-I/MDA5, Toll-like receptor (TLR3)-TRIF, cGAS-STING signaling pathways. suppressed expression IFNs IFN-stimulated genes induced poly (I:C) transfection infection with Sendai virus or virus-like particles. impaired IFN activated components cytosolic dsRNA-sensing pathway, including RIG-I, MDA5, MAVS, but not TBK1, IKKε, IRF3-5D, an active form IRF3. In addition, also TRIF- STING-induced responses. Mechanistically, associated RIG-I MDA5 prevented formation RIG-I/MDA5-MAVS signalosome interacted TRIF STING to inhibit TRIF-TBK1 STING-TBK1 complex formation, thus reducing subsequent IRF3 phosphorylation nuclear translocation are essential for induction. ectopic impeded immune activation facilitated replication. Taken together, dampens responses via disruption signal transduction RIG-I/MDA5-MAVS, TLR3-TRIF, pathways, providing novel insights into interactions between immunity.

Language: Английский

Citations

30
Generation and Functional Analysis of Defective Viral Genomes during SARS-CoV-2 Infection DOI Creative Commons

Terry Zhou,

Nora J. Gilliam,

Sizhen Li

et al.

mBio, Journal Year: 2023, Volume and Issue: 14(3)

Published: April 19, 2023

Defective viral genomes (DVGs) are generated ubiquitously in many RNA viruses, including SARS-CoV-2. Their interference activity to full-length viruses and IFN stimulation provide the potential for them be used novel antiviral therapies vaccine development.

Language: Английский

Citations

28
Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection DOI
Lucy Cooper, Hui Xu, Jack Polmear

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(5), P. 1037 - 1055.e6

Published: April 8, 2024

Language: Английский

Citations

12