Severe COVID-19 Patients Show an Increase in Soluble TNFR1 and ADAM17, with a Relationship to Mortality

Palacios, Yadira; Ruíz, Andy; Ramón‐Luing, Lucero A.; Ocaña-Guzmán, Ranferi; Barreto-Rodríguez, Omar; Sánchez-Monciváis, Anahí; Tecuatzi-Cadena, Brenda; Regalado-García, Ana G; Pineda-Gudiño, Rey David; García-Martínez, Alicia; Juárez-Hernández, Fortunato; Farías-Contreras, Juan Pablo; Fricke-Galindo, Ingrid; Pérez-Rubio, Gloría; Falfán-Valencia, Ramcés; Buendía-Roldán, Ivette; Medina-Quero, Karen; Chávez‐Galán, Leslie

doi:10.3390/ijms22168423

Cited by 39 publications

(36 citation statements)

References 51 publications

(55 reference statements)

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“…It appears that the AA genotype is more prevalent in the Egyptian population studied by Saleh et al 20 variants are high in severe patients. 21 In the current study, the frequency of TNFα genotypes and alleles, comparing between mild and moderate/severe groups were not statistically significant (Table 4). Similarly, no significant differences were found according to genders (Table 5), ages (Table 6), comorbidities (Table 7).…”

Section: Discussioncontrasting

confidence: 52%

“…In the Middle East, particularly in Iraq, studying genetic polymorphisms linking with Covid‐19 infection has been unobserved. Before the Covid‐19 pandemic emerged, our group has been working on genetic polymorphisms in both Toll‐like receptor‐4 (TLR4) and Apolipoprotein Epsilon (ApoE) in a general Kurdish population 18 , 30 ; Lately, we have found that ApoE4 allele is associated with Covid‐19 infection in this population ( 19 Recent studies have found that TNF‐α −308 G > A 20 and TNF receptors 21 are associated with Covid‐19 infections in Egyptian and Mexican populations, respectively. Up to our best knowledge, no studies were conducted on the association of this TNF SNP with Covid‐19 in other ethnic backgrounds.…”

Section: Introductionmentioning

confidence: 99%

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Association of tumor necrosis factor alpha ‐308 single nucleotide polymorphism with SARS CoV‐2 infection in an Iraqi Kurdish population

Ali

Niranji

Al-Jaf

2022

Clinical Laboratory Analysis

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Uncovering risk factors playing roles in the severity of Coronavirus disease 2019 (Covid‐19) are important for understanding pathoimmunology of the disease caused by severe acute respiratory syndrome Coronavirus 2 (SARS CoV‐2). Genetic variations in innate immune genes have been found to be associated with Covid‐19 infections. A single‐nucleotide polymorphism (SNP) in a promoter region of tumor necrosis factor alpha (TNF‐α) gene, TNF‐α −308G>A, increases expression of TNF‐α protein against infectious diseases leading to immune dysregulations and organ damage. This study aims to discover associations between TNF‐α −308G>A SNP and Covid‐19 infection. Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used for genotyping a general Kurdish population and Covid‐19 patients. The homozygous mutant (AA) genotype was found to be rare in the current studied population. Interestingly, the heterozygous (GA) genotype was significantly (p value = 0.0342) higher in the Covid‐19 patients than the general population. This suggests that TNF‐α −308G>A SNP might be associated with Covid‐19 infections. Further studies with larger sample sizes focusing on different ethnic populations are recommended.

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Section: Discussioncontrasting

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Association of tumor necrosis factor alpha ‐308 single nucleotide polymorphism with SARS CoV‐2 infection in an Iraqi Kurdish population

Ali

Niranji

Al-Jaf

2022

Clinical Laboratory Analysis

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“…A recent study on a cohort of 102 Covid-19 patients from Mexico found that ADAM17 is increased in the serum of Covid-19 patients with respect to healthy donors, and in severe patients with respect to mild ones. Possibly as a consequence of this increase, some of the proteins shed in the serum by ADAM17, including TNF-α, its receptors TNFR1 and TNFR2 and T-cell immunoglobulin and mucin domain 3 (TIM3), but not transforming growth factor beta (TGF-β), are increased in the serum of these patients at the protein level while their mRNA is unchanged, which suggests increased ADAM17 activity (Palacios et al, 2021). Moreover, increased level of ADAM17 and its substrates TNFR1 and TIM3 was higher in patients that died of Covid-19 compared with survivors.…”

Section: Increase Of Adam17 In Severe Covid-19 Patientsmentioning

confidence: 99%

Is Covid-19 Severity Associated With ACE2 Degradation?

Bastolla

Chambers

Abia

et al. 2022

Front. Drug Discov.

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Covid-19 is particularly mild with children, and its severity escalates with age. Several theories have been proposed to explain these facts. In particular, it was proposed that the lower expression of the viral receptor ACE2 in children protects them from severe Covid-19. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we review the seemingly contradicting observations on ACE2 expression at the levels of mRNA, membrane protein and serum protein in humans and rodents and try to reconcile them at the light of the Renin-Angiotensin system (RAS) and bradykinin system, which constitute an integrated inflammatory system connected by common peptidases and interacting receptors. We find that ACE2 level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases, consistently with almost all existing data. The increase with age of the protease Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), also known as ADAM17 (a disintegrin and metalloproteinase 17) that sheds ACE2 from the cell membrane to the serum predicts that the decrease occurs before and is steeper for ACE2 cell protein than for its mRNA. This negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF-α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6). Here we propose that ACE2 contributes essentially to reverse this inflammatory state by downregulating the pro-inflammatory peptides of the angiotensin-bradykinin system, and that failure to do this, possibly induced by the degradation of ACE2 by SARS-COV-2, may underlie both severe CoViD-19 infection and its many post-infection manifestations, including the multi-inflammatory syndrome of children (MIS-C). Within this view, lower severity in children despite lower ACE2 expression may be consistent with their higher expression of the alternative angiotensin II receptor ATR2 and in general of the anti-inflammatory arm of the RAS at young age.

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“…This understanding would significantly influence tackling chronic and life-threatening diseases, which were found to be connected to ADAM17, such as cancer and chronic inflammatory diseases like rheumatoid arthritis [12,[51][52][53][54][55]. Recently COVID19 was also associated with an ADAM17 malfunction, which further underlines the current importance of understanding the inhibition mechanism of ADAM17 in detail for external regulation through substrate-specific inhibitors [56][57][58][59][60].…”

Section: Discussionmentioning

confidence: 99%

In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators

Bienstein

Minond

Schwaneberg

et al. 2022

IJMS

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Understanding the mechanisms of modulators’ action on enzymes is crucial for optimizing and designing pharmaceutical substances. The acute inflammatory response, in particular, is regulated mainly by a disintegrin and metalloproteinase (ADAM) 17. ADAM17 processes several disease mediators such as TNFα and APP, releasing their soluble ectodomains (shedding). A malfunction of this process leads to a disturbed inflammatory response. Chemical protease inhibitors such as TAPI-1 were used in the past to inhibit ADAM17 proteolytic activity. However, due to ADAM17′s broad expression and activity profile, the development of active-site-directed ADAM17 inhibitor was discontinued. New ‘exosite’ (secondary substrate binding site) inhibitors with substrate selectivity raised the hope of a substrate-selective modulation as a promising approach for inflammatory disease therapy. This work aimed to develop a high-throughput screen for potential ADAM17 modulators as therapeutic drugs. By combining experimental and in silico methods (structural modeling and docking), we modeled the kinetics of ADAM17 inhibitor. The results explain ADAM17 inhibition mechanisms and give a methodology for studying selective inhibition towards the design of pharmaceutical substances with higher selectivity.

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Severe COVID-19 Patients Show an Increase in Soluble TNFR1 and ADAM17, with a Relationship to Mortality

Cited by 39 publications

References 51 publications

Association of tumor necrosis factor alpha ‐308 single nucleotide polymorphism with SARS CoV‐2 infection in an Iraqi Kurdish population

Association of tumor necrosis factor alpha ‐308 single nucleotide polymorphism with SARS CoV‐2 infection in an Iraqi Kurdish population

Is Covid-19 Severity Associated With ACE2 Degradation?

In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators

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