Correlation of Low Levels of α-1 Antitrypsin and Elevation of Neutrophil to Lymphocyte Ratio with Higher Mortality in Severe COVID-19 Patients

Shimi, Ghazaleh; Sohrab, Golbon; Pourvali, Katayoun; Ghorbani, Abdolbaset; Balam, Farinaz Hosseini; Rostami, Khalil; Zand, Hamid

doi:10.1155/2021/5555619

Cited by 8 publications

(8 citation statements)

References 38 publications

(42 reference statements)

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“…Given our findings and the previously mentioned studies showing that those with AAT deficiency are more predisposed to severe disease and death from COVID-19, it is reasonable to surmise that AAT augmentation in those with severe AAT deficiency would be beneficial against COVID-19. Nevertheless, even in the absence of frank AAT deficiency, the AAT response to a systemic infection may be inadequate as has been shown for hospitalized COVID-19 patients 40 and among millions with certain heterozygous AAT mutations 41 . This possibility leads to the question of whether AAT supplementation would be beneficial even in those without frank AAT deficiency?…”

Section: Discussionmentioning

confidence: 99%

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19

Bai

Buckle

Vladar

et al. 2022

Sci Rep

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The cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin–TMPRSS2–AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2–AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19.

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Section: Discussionmentioning

confidence: 99%

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19

Bai

Buckle

Vladar

et al. 2022

Sci Rep

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“…AAT plasma levels can normally increase 3-to 5-fold in the course of systemic inflammation and/or infection, however, AAT was observed to be present at low levels in severe cases of COVID-19 [237]. In agreement with these findings, Vianello and Braccioni [238] showed that, in Italy, there was a geographic co-localization between individuals with AAT deficiency and the number of COVID-19 cases.…”

Section: Secretory Leucocyte Protease Inhibitor (Slpi)mentioning

confidence: 64%

“…In agreement with these findings, Vianello and Braccioni [238] showed that, in Italy, there was a geographic co-localization between individuals with AAT deficiency and the number of COVID-19 cases. Interestingly, AAT serum levels can be modulated by genetic variants as well as by cigarette exposure, oxidative stress and pollution, and these changes may have a significant relevance in lowering the protective role of AAT during COVID-19 [234,237]. Since AAT irreversibly inhibits serine proteases and elastases, but may also exert anti-viral, anti-TMPRSS-2, anti-inflammatory, anti-thrombin, anti-NETs and antiapoptotic activities, AAT represents an additional candidate for the treatment of COVID-19 [234].…”

Section: Secretory Leucocyte Protease Inhibitor (Slpi)mentioning

confidence: 99%

The “Elastic Perspective” of SARS-CoV-2 Infection and the Role of Intrinsic and Extrinsic Factors

Boraldi

Lofaro

Cossarizza

et al. 2022

IJMS

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Elastin represents the structural component of the extracellular matrix providing elastic recoil to tissues such as skin, blood vessels and lungs. Elastogenic cells secrete soluble tropoelastin monomers into the extracellular space where these monomers associate with other matrix proteins (e.g., microfibrils and glycoproteins) and are crosslinked by lysyl oxidase to form insoluble fibres. Once elastic fibres are formed, they are very stable, highly resistant to degradation and have an almost negligible turnover. However, there are circumstances, mainly related to inflammatory conditions, where increased proteolytic degradation of elastic fibres may lead to consequences of major clinical relevance. In severely affected COVID-19 patients, for instance, the massive recruitment and activation of neutrophils is responsible for the profuse release of elastases and other proteolytic enzymes which cause the irreversible degradation of elastic fibres. Within the lungs, destruction of the elastic network may lead to the permanent impairment of pulmonary function, thus suggesting that elastases can be a promising target to preserve the elastic component in COVID-19 patients. Moreover, intrinsic and extrinsic factors additionally contributing to damaging the elastic component and to increasing the spread and severity of SARS-CoV-2 infection are reviewed.

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“…Indeed, several studies pointed to a tentative link between lower blood AAT levels and severe Covid-19, suggesting that AAT deficiency contributes to Covid-19 fatalities (Faria et al, 2021;Ferrarotti et al, 2021;Shapira et al, 2020;Shimi et al, 2021;Vianello & Braccioni, 2020). Indeed, bioengineered AAT, which is approved for treating lung inflammation in AAT deficient individuals, was proposed as potential therapeutic for Covid-19 (Marzouk et al, 2021;Yang et al, 2020;Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The reduced expression of SERPINA1 , coding for alpha‐1 antitrypsin (AAT), observed following chronic d ‐galactose treatment, also suggests higher SARS‐CoV‐2 infection load: AAT readily inhibits TMPRSS2 (Azouz et al, 2021; Wettstein et al, 2021), which is essential for priming SARS‐CoV‐2 for cell entry (Azouz et al, 2021; Hoffmann et al, 2020). Indeed, several studies pointed to a tentative link between lower blood AAT levels and severe Covid‐19, suggesting that AAT deficiency contributes to Covid‐19 fatalities (Faria et al, 2021; Ferrarotti et al, 2021; Shapira et al, 2020; Shimi et al, 2021; Vianello & Braccioni, 2020). Indeed, bioengineered AAT, which is approved for treating lung inflammation in AAT deficient individuals, was proposed as potential therapeutic for Covid‐19 (Marzouk et al, 2021; Yang et al, 2020; Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

Baristaite

Genevieve

2021

Drug Dev Res

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Several comorbidities including diabetes, immune deficiency, and chronic respiratory disorders increase the risk of severe Covid‐19 and fatalities among SARS‐CoV‐2 infected individuals. Severe Covid‐19 risk among diabetes patients may reflect reduced immune response to viral infections. SARS‐CoV‐2 initially infects respiratory tract epithelial cells by binding to the host cell membrane ACE2, followed by proteolytic priming for cell entry by the host cell membrane serine protease TMPRSS2. Additionally, the protease FURIN facilitates cell exit of mature SARS‐CoV‐2 virions. Alpha‐1 antitrypsin (AAT), the major plasma serine protease inhibitor, encoded by SERPINA1, is known to promote immune response to viral infections. AAT inhibits neutrophil elastase, a key inflammatory serine protease implicated in alveolar cell damage during respiratory infections, and AAT deficiency is associated with susceptibility to lung infections. AAT is implicated in Covid‐19 as it inhibits TMPRSS2, a protease essential for SARS‐CoV‐2 cell entry. Here we show that treatment of A549 human lung epithelial cells for 7 days with 25 mM d‐galactose, an inducer of diabetic‐like and oxidative stress cellular phenotypes, leads to increased mRNA levels of ACE2, TMPRSS2, and FURIN, along with reduced SERPINA1 mRNA. Together, the dysregulated transcription of these genes following d‐galactose treatment suggests that chronic diabetic‐like conditions may facilitate SARS‐CoV‐2 infection of lung epithelial cells. Our findings may in part explain the higher severe Covid‐19 risk in diabetes, and highlight the need to develop special treatment protocols for diabetic patients.

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Correlation of Low Levels of α-1 Antitrypsin and Elevation of Neutrophil to Lymphocyte Ratio with Higher Mortality in Severe COVID-19 Patients

Cited by 8 publications

References 38 publications

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19

Enoxaparin augments alpha-1-antitrypsin inhibition of TMPRSS2, a promising drug combination against COVID-19

The “Elastic Perspective” of SARS-CoV-2 Infection and the Role of Intrinsic and Extrinsic Factors

d‐Galactose treatment increasesACE2,TMPRSS2, andFURINand reducesSERPINA1mRNAexpression inA549human lung epithelial cells

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