Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(7), С. 3507 - 3507

Опубликована: Март 23, 2022

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of most devastating pandemics recent times. The lack potent novel antivirals had led to global health crises; however, emergence and approval inhibitors viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in therapeutic front but also context prophylaxis against infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, lessons learnt from previous currently ongoing taught us that these can easily escape selection pressure through vital target amino acid residues monotherapeutic settings. In this paper, we review nirmatrelvir its binding SARS-CoV-2 Mpro draw a comparison HIV were rendered obsolete resistance mutations, emphasizing potential pitfalls design may be important relevance long-term use SARS-CoV-2.

Язык: Английский

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SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1

Cellular and Molecular Immunology, Год журнала: 2022, Номер 19(8), С. 872 - 882

Опубликована: Июнь 23, 2022

Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome (ARDS)-related failure. Cytokine storms and oxidative stress major players in ARDS development during virus infections. However, it is still unknown how regulated by viral host factors response SARS-CoV-2 infection. Here, we found that activation of NRF2/HMOX1 significantly suppressed replication multiple cell types producing metabolite biliverdin, whereas impaired axis through action nonstructural protein NSP14. Mechanistically, NSP14 interacts with catalytic domain NAD-dependent deacetylase Sirtuin 1 (SIRT1) inhibits its ability activate pathway. Furthermore, both genetic pharmaceutical evidence corroborated novel antiviral activity SIRT1 against SARS-CoV-2. Therefore, our findings reveal a mechanism which dysregulates antioxidant defense system emphasize vital role played SIRT1/NRF2

Язык: Английский

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Interferon induction, evasion, and paradoxical roles during SARS‐CoV‐2 infection*

Immunological Reviews, Год журнала: 2022, Номер 309(1), С. 12 - 24

Опубликована: Июль 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

Язык: Английский

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Pyroptotic cell death in SARS-CoV-2 infection: revealing its roles during the immunopathogenesis of COVID-19

International Journal of Biological Sciences, Год журнала: 2022, Номер 18(15), С. 5827 - 5848

Опубликована: Янв. 1, 2022

The rapid dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent disease 2019 , remains a global public health emergency.The host immune response to SARS-CoV-2 plays key role in COVID-19 pathogenesis.SARS-CoV-2 can induce aberrant and excessive responses, leading cytokine storm syndrome, autoimmunity, lymphopenia, neutrophilia dysfunction monocytes macrophages.Pyroptosis, proinflammatory form programmed cell death, acts as defense mechanism against infections.Pyroptosis deprives replicative niche by inducing lysis infected cells exposing virus extracellular attack.Notably, has evolved sophisticated mechanisms hijack this death mode for its own survival, propagation shedding.SARS-CoV-2-encoded viral products act modulate various components pyroptosis pathways, including inflammasomes, caspases gasdermins.SARS-CoV-2-induced contriubtes development COVID-19-associated immunopathologies through leakage intracellular contents, disruption system homeostasis or exacerbation inflammation.Therefore, emerged an important involved immunopathogenesis.However, entangled links between pathogenesis lack systematic clarification.In review, we briefly summarize characteristics COVID-19-related immunopathologies.Moreover, present overview interplay infection highlight recent research advances understanding responsible implication pathways pathogenesis, which will provide informative inspirations new directions further investigation clinical practice.Finally, discuss potential value therapeutic target COVID-19.An in-depth discussion underlying be conducive identification targets exploration effective treatment measures aimed at conquering SARS-CoV-2-induced COVID-19.

Язык: Английский

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The Role of Coinhibitory Receptors in B Cell Dysregulation in SARS-CoV-2–Infected Individuals with Severe Disease

The Journal of Immunology, Год журнала: 2024, Номер 212(10), С. 1540 - 1552

Опубликована: Март 22, 2024

Abstract Severe SARS-CoV-2 infection is associated with significant immune dysregulation involving different cell subsets. In this study, when analyzing critically ill COVID-19 patients versus those mild disease, we observed a reduction in total and memory B subsets but an increase naive cells. Moreover, cells from displayed impaired effector functions, evidenced by diminished proliferative capacity, reduced cytokine, Ab production. This functional impairment was accompanied increased apoptotic potential upon stimulation severely patients. Our further studies revealed the expansion of expressing coinhibitory molecules (PD-1, PD-L1, TIM-1, VISTA, CTLA-4, Gal-9) intensive care unit (ICU)–admitted not disease. The receptor expression linked to altered IgA IgG capacity Also, found frequency CD24hiCD38hi regulatory IL-10 mechanistic that upregulation PD-L1 elevated plasma IL-6 levels implies connection between cytokine storm phenotype function. Finally, our metabolomic analysis showed tryptophan elevation kynurenine ICU-admitted We promotes cells, correlating IL-6R STAT1/STAT3 activation. observations provide novel insights into complex interplay dysregulation, implicating receptors, IL-6, potentially contributing pathogenesis COVID-19.

Язык: Английский

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Role of interferons in the antiviral battle: from virus-host crosstalk to prophylactic and therapeutic potential in SARS-CoV-2 infection

Frontiers in Immunology, Год журнала: 2024, Номер 14

Опубликована: Янв. 15, 2024

Mammalians sense antigenic messages from infectious agents that penetrate the respiratory and digestive epithelium, as well signals damaged host cells through membrane cytosolic receptors. The transduction of these triggers a personalized response, depending on nature stimulus host’s genetics, physiological condition, comorbidities. Interferons (IFNs) are primary effectors innate immune their synthesis is activated in most within few hours after pathogen invasion. IFNs primarily synthesized infected cells, but anti-infective effect extended to neighboring by autocrine paracrine action. emergence severe acute syndrome coronavirus 2 (SARS‐CoV‐2) pandemic 2019 was stark reminder potential threat posed newly emerging viruses. This has also triggered an overwhelming influx research studies aiming unveil mechanisms protective versus pathogenic responses induced SARS‐CoV‐2. purpose this review describe role vital players battle against SARS‐CoV-2 infection. We will briefly characterize classify IFNs, present inductors IFN synthesis, sensors, signaling pathways, then discuss controlling evolution SARS-CoV-2 infection its clinical outcome. Finally, we perspectives controversies regarding prophylactic therapeutic

Язык: Английский

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New insights into the pathogenesis of SARS-CoV-2 during and after the COVID-19 pandemic

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июнь 7, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the distress condition known as COVID-19. This disease broadly affects several physiological systems, including gastrointestinal, renal, and central nervous (CNS) significantly influencing patient’s overall quality of life. Additionally, numerous risk factors have been suggested, gender, body weight, age, metabolic status, renal health, preexisting cardiomyopathies, inflammatory conditions. Despite advances in understanding genome pathophysiological ramifications COVID-19, its precise origins remain elusive. SARS-CoV-2 interacts with a receptor-binding domain within angiotensin-converting enzyme (ACE2). receptor expressed various organs different species, humans, abundance. Although COVID-19 has multiorgan manifestations, main pathologies occur lung, pulmonary fibrosis, failure, embolism, secondary bacterial pneumonia. In post-COVID-19 period, sequelae may occur, which causes, direct action virus, alteration immune response, alterations during infection, among others. Recognizing serious adverse health effects associated it becomes imperative to comprehensively elucidate discuss existing evidence surrounding this viral those related subsequent consequences. review aims contribute comprehensive impact long-term on human health.

Язык: Английский

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SARS-CoV-2 infection and immune responses

AIMS Microbiology, Год журнала: 2023, Номер 9(2), С. 245 - 276

Опубликована: Янв. 1, 2023

<abstract> <p>The recent pandemic caused by the SARS-CoV-2 virus continues to be an enormous global challenge faced healthcare sector. Availability of new vaccines and drugs targeting sequelae COVID-19 has given world hope in ending pandemic. However, emergence mutations viral genome every couple months different parts is a persistent danger public health. Currently there no single treatment eradicate risk COVID-19. The widespread transmission due Omicron variant necessitates continued work on development implementation effective vaccines. Moreover, evidence that receptor domain spike glycoprotein led decrease current vaccine efficacy escaping antibody recognition. Therefore, it essential actively identify mechanisms which evades host immune system, study long-lasting effects develop therapeutics infections humans preclinical models. In this review, we describe pathogenic infection as well innate adaptive responses infection. We address ongoing need provide protection against variants SARS-CoV-2, validated endpoint assays evaluate immunogenicity pipeline, medications, anti-viral drug therapies health measures, will required successfully end pandemic.</p> </abstract>

Язык: Английский

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Broad antagonism of coronaviruses nsp5 to evade the host antiviral responses by cleaving POLDIP3

PLoS Pathogens, Год журнала: 2023, Номер 19(10), С. e1011702 - e1011702

Опубликована: Окт. 6, 2023

Coronaviruses (CoVs) are a family of the largest RNA viruses that typically cause respiratory, enteric, and hepatic diseases in animals humans, imposing great threats to public safety animal health. Porcine deltacoronavirus (PDCoV), newly emerging enteropathogenic coronavirus, causes severe diarrhea suckling piglets all over world poses potential risks cross-species transmission. Here, we use PDCoV as model CoVs illustrate reciprocal regulation between infection host antiviral responses. In this study, downregulation DNA polymerase delta interacting protein 3 (POLDIP3) was confirmed infected IPEC-J2 cells by isobaric tags for relative absolute quantification (iTRAQ) Western blotting analysis. Overexpression POLDIP3 inhibits infection, whereas knockout (POLDIP3-/-) CRISPR-Cas9 editing significantly promotes indicating novel regulator against infection. Surprisingly, an antagonistic strategy revealed encoded nonstructural 5 (nsp5) responsible reduction via its 3C-like protease cleavage at glutamine acid 176 (Q176), facilitating due loss effects cleaved fragments. Consistent with obtained data cell vitro, also corroborated infected-SPF vivo. Collectively, unveiled new evolved counteract innate immunity nsp5-mediated cleavage, eventually ensuring productive virus replication. Importantly, further demonstrated nsp5s from PEDV TGEV harbor conserved function cleave porcine Q176 despair POLDIP3-mediated effects. addition, nsp5 SARS-CoV-2 cleaves human POLDIP3. Therefore, speculate coronaviruses employ similar mechanisms mediated antagonize responses sustain efficient

Язык: Английский

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Innate immune recognition against SARS-CoV-2

Inflammation and Regeneration, Год журнала: 2023, Номер 43(1)

Опубликована: Янв. 26, 2023

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative virus of pandemic disease called coronavirus 2019 (COVID-19). Most infected individuals have asymptomatic or mild symptoms, but some patients show severe and critical systemic inflammation including tissue damage multi-organ failures. Immune responses to pathogen determine clinical course. In general, activation innate immune mediated by host pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) as well damage-associated (DAMPs), which results in downstream gene induction programs types I III interferons (IFNs) proinflammatory cytokines for inducing antiviral activity. However, excessive these may lead deleterious inflammation. Here, we review recent advances our understanding SARS-CoV-2 infection, particularly terms recognition subsequent underlying COVID-19 immunopathology.

Язык: Английский

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