Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

Journal of Biomedical Science, Год журнала: 2021, Номер 28(1)

Опубликована: Янв. 12, 2021

Abstract Background Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology COVID-19 will support design rational treatments targeting life cycle virus and/or adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) other pathologies. Main body is a two-phase disease being marked ( phase 1 ) increased transmission rates due to wide expression main infection-related ACE2 , TMPRSS2 CTSB/L human genes in tissues gastrointestinal tract, as well 2 host- probably sex- age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation (due broad organotropism SARS-CoV-2) collateral tissue damage systemic failure likely because imbalanced ACE/ANGII/AT1R ACE2/ANG(1–7)/MASR axes signaling. Conclusion Here we discuss number approaches aiming suppress viral or propagation; increase antigen presentation order activate robust durable adaptive response from host, mitigate ARDS-related “cytokine storm” triggers severe life-threatening complications COVID-19.

Язык: Английский

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SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1716 - 1716

Опубликована: Фев. 2, 2022

The review aims to consolidate research findings on the molecular mechanisms and virulence pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome 2 (SARS-CoV-2), their relevance four typical stages in development viral infection. These are invasion; primary blockade antiviral innate immunity; engagement virus’s protection against factors adaptive acute, long-term complications COVID-19. invasion stage entails recognition spike protein (S) SARS-CoV-2 target cell receptors, namely, main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, potential alternative receptors. presence a diverse repertoire receptors allows infect various types cells, including those not expressing ACE2. During second stage, majority polyfunctional structural, non-structural, extra proteins synthesizes infected cells involved blockage immunity. A high degree redundancy systemic action characterizing these pathogenic overcome at initial invasion. third includes passive active virus from immunity, overcoming barrier function focus inflammation, generalization body. fourth is associated with deployment variants SARS-CoV-2’s ability induce autoimmune autoinflammatory pathways tissue both immunosuppressive hyperergic inflammation critical this

Язык: Английский

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No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor

Scientific Reports, Год журнала: 2021, Номер 11(1)

Опубликована: Янв. 11, 2021

The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding host receptors including ACE2. An alternate entry receptor for the virus was recently proposed be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on role this in infection pathogenesis. Here, we report that are unable find evidence supporting basigin as putative receptor. Recombinant forms do not interact with expressed surface cells, by using specialized assays tailored detect interactions weak or weaker than basigin-spike binding, no interaction between either two common isoforms basigin. Finally, removing from lung epithelial CRISPR/Cas9 results change their susceptibility infection. Given pressing need clarity which targets may lead promising therapeutics, present these findings allow more informed decisions about translational relevance mechanism race understand treat COVID-19.

Язык: Английский

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The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

Journal of Biological Chemistry, Год журнала: 2021, Номер 296, С. 100759 - 100759

Опубликована: Янв. 1, 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 global pandemic, utilizes host receptor angiotensin-converting enzyme (ACE2) for viral entry. However, other factors might also play important roles in SARS-CoV-2 infection, providing new directions antiviral treatments. GRP78 is a stress-inducible chaperone entry and infectivity many viruses. Recent molecular docking analyses revealed putative interaction between receptor-binding domain (RBD) Spike protein (SARS-2-S). Here we report that can form complex with SARS-2-S ACE2 on surface at perinuclear region typical endoplasmic reticulum VeroE6-ACE2 cells substrate-binding critical this interaction. In vitro binding studies further confirmed directly bind to RBD ACE2. To investigate role complex, knocked down cells. Loss markedly reduced cell expression led activation markers unfolded response. Treatment lung epithelial humanized monoclonal antibody (hMAb159) selected its safe clinical profile preclinical models depleted expression, as well SARS-2-S-driven infection vitro. Our data suggest an auxiliary factor potential target combat novel pathogen viruses utilize combination therapy.

Язык: Английский

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Role of Hypertension on the Severity of COVID-19: A Review

Journal of Cardiovascular Pharmacology, Год журнала: 2021, Номер 78(5), С. e648 - e655

Опубликована: Июль 29, 2021

Abstract: The novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) has rapidly evolved into a global pandemic. substantial morbidity and mortality associated with infection prompted us to understand potential risk factors that can predict patient outcomes. Hypertension been identified as most prevalent cardiovascular comorbidity in patients infected COVID-19 demonstrably increases of hospitalization death. Initial studies implied renin–angiotensin–aldosterone system inhibitors might increase viral aggravate severity, thereby causing panic given high prevalence hypertension. Nonetheless, subsequent evidence supported administration antihypertensive drugs noted they do not severity hypertension, rather may have beneficial effect. To date, precise mechanism which hypertension predisposes unfavorable outcomes remains unknown. In this mini review, we elaborate on pathology SARS-CoV-2 coexisting summarize mechanisms, focusing dual roles angiotensin-converting enzyme disorders effects proinflammatory released because immune response gastrointestinal dysfunction are also discussed.

Язык: Английский

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ACE2 protein expression in lung tissues of severe COVID-19 infection

Scientific Reports, Год журнала: 2022, Номер 12(1)

Опубликована: Март 8, 2022

Abstract Angiotensin-converting enzyme 2 (ACE2) is a key host protein by which severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters and multiplies within cells. The level of ACE2 expression in the lung hypothesised to correlate with an increased risk infection complications COrona VIrus Disease 2019 (COVID-19). To test this hypothesis, we compared status immunohistochemistry (IHC) post-mortem samples patients who died COVID-19 obtained from non-COVID-19 for other indications. IHC CD61 CD163 was performed assessment platelet-rich microthrombi macrophages, respectively. SARS-CoV-2 viral antigen also performed. In total 55, 44 were tested ACE2, 36 CD163, 26 CD61, 15 non-covid 19 control sections. Quantification immunostaining, random sampling, correlation analysis used substantiate morphologic findings. Our results show that significantly higher tissues than controls, regardless sample size. Histomorphology lungs showed diffuse alveolar damage (DAD), bronchopneumonia, injury detected subset cases. levels positively correlated CD163. conclusion, our disease, correlating macrophage infiltration microthrombi, suggesting pathobiological role disease severity.

Язык: Английский

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Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases

Cell Communication and Signaling, Год журнала: 2023, Номер 21(1)

Опубликована: Май 15, 2023

Coronavirus disease 2019 (COVID-19) is caused by a new member of the Coronaviridae family known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are structural and non-structural proteins (NSPs) in genome this virus. S, M, H, E proteins, NSPs include accessory replicase proteins. The NSP components SARS-CoV-2 play an important role its infectivity, some them may be pathogenesis chronic diseases, including cancer, coagulation disorders, neurodegenerative cardiovascular diseases. interact with targets such angiotensin-converting enzyme (ACE2) receptor. In addition, can stimulate pathological intracellular signaling pathways triggering transcription factor hypoxia-inducible factor-1 (HIF-1), neuropilin-1 (NRP-1), CD147, Eph receptors, which roles progression diseases like Alzheimer's disease, epilepsy, multiple sclerosis, cancers glioblastoma, lung malignancies, leukemias. Several compounds polyphenols, doxazosin, baricitinib, ruxolitinib could inhibit these interactions. It has been demonstrated that spike protein stronger affinity for human ACE2 than SARS-CoV, leading current study to hypothesize newly produced variant Omicron receptor-binding domain (RBD) binds more strongly primary strain. SARS Middle East (MERS) viruses against have become resistant previous vaccines. Therefore, review recent studies performance vaccines their effects on COVID-19 related vital need deal conditions. This examines potential initiation it anticipated serve effective vaccine or treatment Video Abstract.

Язык: Английский

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The role of cell surface sialic acids for SARS-CoV-2 infection

Glycobiology, Год журнала: 2021, Номер 31(10), С. 1245 - 1253

Опубликована: Апрель 13, 2021

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a new virus that has higher contagious capacity than any other previous human coronaviruses (HCoVs) and causes the current coronavirus disease 2019 pandemic. Sialic acids are group of nine-carbon acidic α-keto sugars, usually located at end glycans cell surface glycoconjugates serve as attachment sites for HCoVs. It therefore speculated sialic on host could co-receptors or factors SARS-CoV-2 entry well. Recent in silico modeling, molecular modeling predictions microscopy studies indicate potential acid binding by upon entry. In particular, flat acid-binding domain was proposed N-terminal spike protein, which may lead to initial contact interaction epithelium followed affinity angiotensin-converting enzyme 2 (ACE2) receptor, likely two-step fashion. However, recent vitro ex vivo ACE2 receptor confirmed an opposite role binding. neuraminidase treatment epithelial cells ACE2-expressing 293T increased Furthermore, glycosylation inhibition prevent ACE2–spike protein interaction. On hand, most study indicates gangliosides ligands receptor-binding protein. This mini-review discusses what been predicted known so far about infection future research perspective.

Язык: Английский

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Not only ACE2—the quest for additional host cell mediators of SARS-CoV-2 infection: Neuropilin-1 (NRP1) as a novel SARS-CoV-2 host cell entry mediator implicated in COVID-19

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Янв. 18, 2021

Язык: Английский

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The Mechanism of SARS-CoV-2 Nucleocapsid Protein Recognition by the Human 14-3-3 Proteins

Journal of Molecular Biology, Год журнала: 2021, Номер 433(8), С. 166875 - 166875

Опубликована: Фев. 5, 2021

The coronavirus nucleocapsid protein (N) controls viral genome packaging and contains numerous phosphorylation sites located within unstructured regions. Binding of phosphorylated SARS-CoV N to the host 14-3-3 in cytoplasm was reported regulate nucleocytoplasmic shuttling. All seven isoforms human are abundantly present tissues vulnerable SARS-CoV-2, where can constitute up ~1% expressed proteins during infection. Although association between SARS-CoV-2 represent one key host-pathogen interactions, its molecular mechanism specific critical phosphosites unknown. Here, we show that (pN) dimers, reconstituted via bacterial co-expression with kinase A, directly associate, a phosphorylation-dependent manner, dimeric protein, but not monomeric mutant. We demonstrate pN is recognized by all various efficiencies deduce apparent KD selected isoforms, showing these low micromolar range. Serial truncations pinpointed site Ser197, which conserved among related zoonotic coronaviruses functionally important, SR-rich region N. relatively tight 14-3-3/pN could shuttling other functions occlusion region, also hijack cellular pathways sequestration. As such, assembly may valuable target for therapeutic intervention.

Язык: Английский

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