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1.
Rev Med Virol ; 31(6): e2221, 2021 11.
Article in English | MEDLINE | ID: covidwho-1575100

ABSTRACT

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , C-Reactive Protein/antagonists & inhibitors , COVID-19/drug therapy , Complement System Proteins/immunology , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/pathogenicity , ADAM17 Protein/antagonists & inhibitors , ADAM17 Protein/genetics , ADAM17 Protein/immunology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Biomarkers/blood , C-Reactive Protein/genetics , C-Reactive Protein/immunology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Celecoxib/therapeutic use , Complement System Proteins/genetics , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Disease Progression , Doxycycline/therapeutic use , Gene Expression Regulation , Humans , Randomized Controlled Trials as Topic , Severity of Illness Index , Survival Analysis
2.
Am J Ther ; 28(3): e358-e360, 2020 Aug 03.
Article in English | MEDLINE | ID: covidwho-1349825

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly expanding global health crisis. A disintegrin and metalloproteinase 17 (ADAM17), an ectodomain sheddase, is a key component of ACE2 modulation and plays a complex role in inflammation and immunosurveillance. AREAS OF UNCERTAINTY: Much remains unknown regarding the immunopathogenesis of COVID-19, including how the virus affects ADAM17 expression, activity, and regulation. SEARCH STRATEGY: Three electronic databases (MEDLINE through PubMed, Embase through Ovid, and Google Scholar) were searched to identify articles relevant to ADAM17 and severe acute respiratory syndrome coronavirus 1 and 2. Relevant articles published from January 1, 2005, to April 30, 2020, were selected, and reference lists were screened and cross-referenced. We also searched preprint studies on medRxiv and bioRxiv given the rapidly evolving data on COVID-19 SARS-CoV-2. THERAPEUTIC OPINION: Infection with SARS-CoV-2 may lead to an increase in ADAM17 sheddase activity contributing to an exuberant macrophage-predominant inflammatory response and diminished immunosurveillance capacity for viral clearance. Emerging data suggest severe lung injury in COVID-19 is associated with higher levels of TNF-α and IL-6, T-cell lymphopenia and exhaustion, hypercoagulability, and a macrophage-predominant immune response. This clinical picture is consistent with dysregulation of many of the molecular pathways in which ADAM17 participates. CONCLUSIONS: Elucidation of the role of ADAM17 in COVID-19 may identify novel molecular targets for drug development and therapeutic repurposement.


Subject(s)
ADAM17 Protein , COVID-19 , SARS-CoV-2/physiology , Signal Transduction/immunology , ADAM17 Protein/immunology , ADAM17 Protein/metabolism , COVID-19/immunology , COVID-19/virology , Drug Discovery , Gene Expression , Humans , Immunity
3.
Int J Mol Sci ; 22(16)2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1341695

ABSTRACT

Overproduction of inflammatory cytokines is a keystone event in COVID-19 pathogenesis; TNF and its receptors (TNFR1 and TNFR2) are critical pro-inflammatory molecules. ADAM17 releases the soluble (sol) forms of TNF, TNFR1, and TNFR2. This study evaluated TNF, TNFRs, and ADAM17 at the protein, transcriptional, and gene levels in COVID-19 patients with different levels of disease severity. In total, 102 patients were divided into mild, moderate, and severe condition groups. A group of healthy donors (HD; n = 25) was included. Our data showed that solTNFR1 and solTNFR2 were elevated among the COVID-19 patients (p < 0.0001), without increasing the transcriptional level. Only solTNFR1 was higher in the severe group as compared to the mildly ill (p < 0.01), and the level was higher in COVID-19 patients who died than those that survived (p < 0.0001). The solTNFR1 level had a discrete negative correlation with C-reactive protein (p = 0.006, Rho = -0.33). The solADAM17 level was higher in severe as compared to mild disease conditions (p < 0.01), as well as in COVID-19 patients who died as compared to those that survived (p < 0.001). Additionally, a potential association between polymorphism TNFRSF1A:rs767455 and a severe degree of disease was suggested. These data suggest that solTNFR1 and solADAM17 are increased in severe conditions. solTNFR1 should be considered a potential target in the development of new therapeutic options.


Subject(s)
ADAM17 Protein , COVID-19/immunology , Receptors, Tumor Necrosis Factor, Type I , Tumor Necrosis Factor-alpha , ADAM17 Protein/blood , ADAM17 Protein/immunology , Adult , Aged , Case-Control Studies , Cohort Studies , Female , Humans , Male , Middle Aged , Receptors, Tumor Necrosis Factor, Type I/blood , Severity of Illness Index , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology
4.
Med Hypotheses ; 144: 110044, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-623607

ABSTRACT

The SARS-CoV-2 hyperinflammatory response is associated with high mortality. This hypothesis suggests that a deficiency of nicotinamide adenine dinucleotide (NAD+) may be the primary factor related to the SARS-Cov-2 disease spectrum and the risk for mortality, as subclinical nutritional deficiencies may be unmasked by any significant increase in oxidative stress. NAD+ levels decline with age and are also reduced in conditions associated with oxidative stress as occurs with hypertension, diabetes and obesity. These groups have also been observed to have high mortality following infection with COVID-19. Further consumption of NAD+ in a pre-existent depleted state is more likely to cause progression to the hyperinflammatory stage of the disease through its limiting effects on the production of SIRT1. This provides a unifying hypothesis as to why these groups are at high risk of mortality and suggests that nutritional support with NAD+ and SIRT1 activators, could minimise disease severity if administered prophylactically and or therapeutically. The significance of this, if proven, has far-reaching consequences in the management of COVID-19 especially in third world countries, where resources and finances are limited.


Subject(s)
COVID-19/immunology , Diabetes Mellitus, Type 2/complications , NAD/deficiency , Obesity/complications , Sirtuin 1/immunology , ADAM17 Protein/immunology , ADP-ribosyl Cyclase 1/immunology , Age Factors , Aged , Aging , COVID-19/mortality , Diabetes Mellitus, Type 2/immunology , Disease Progression , Disease Susceptibility , Humans , Inflammation , Membrane Glycoproteins/immunology , NAD/chemistry , Obesity/immunology , Oxidative Stress , Protein Binding , Virus Replication , Zinc/chemistry
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