A1AT is thought to be involved in the pathogenesis of COVID-19 because of its role as an innate immune system regulator, its function in lung homeostasis, and its potential relevance to the RAS system.  It may have a protective effect against SARS-CoV-2 infections by inhibiting the function of TMPRSS2 and TMPRSS2.  By inhibiting the serine protease ADAM17, which is involved in the viral uptake, the virus may be less efficient in infecting cells or may be prevented from infecting cells.  By inhibiting the sheddase ADAM17,  ACE2 cleavage would be controlled and may protect certain tissues from RAS system imbalance.  Additionally, inhibiting ADAM17 would prevent TNF‐α and IL6R cleavage which would have an anti-inflammatory effect which could ameliorate COVID-19 cytokine storm.  A1AT may also inhibit neutrophil elastase (NE), an enzyme that may be involved in SARS-CoV-2 S protein cleavage.  

A1AT in the Pathogenesis of COVID-19

A1AT has been demonstrated to play a protective role against different viral infections.  It was shown to lessen HIV replication by binding to the viral glycoprotein gp41.  This prevented the virus from being able to enter host cells.  A1AT played a protective role in human rhinovirus (HRV) infections in airway epithelial cells in vitro.  These cells had reduced ICAM‐1 expression which is used by the virus for cell entry.  In normal physiology, this molecule modulates vascular permeability and immune responses.

Michigan State University

Alpha-1-antitrypsin (A1AT) is a serine protease inhibitor that is made in the endoplasmic reticulum and then released by the Golgi apparatus.  In normal physiology, A1AT primarily works to inactivate proteolytic enzymes.  This is particularly relevant to pulmonary tissues which are constantly exposed to potential pathogens and have a high rate of cellular immune activity.  A1AT notably inhibits the function of neutrophil elastase (NE) which suggests that it may be related to pulmonary disease states such as fibrosis.  

Alpha‐1‐Antitrypsin (A1AT)

de Loyola, M. B., dos Reis, T. T. A., de Oliveira, G. X. L. M., da Fonseca Palmeira, J., Argañaraz, G. A., & Argañaraz, E. R. Alpha‐1‐antitrypsin: A possible host protective factor against Covid‐19. Reviews in Medical Virology, e2157.
https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2157
doi: 10.1002/rmv.2157

Alpha‐1‐antitrypsin: A possible host protective factor against Covid‐19

A1AT has more than 100 allele variants that result in unique A1AT blood plasma levels.  M1-M6 are considered normal variants of the enzyme and result in plasma levels ≥0.9 mg/mL.  Null mutations are not common.  Additionally, about 70% of aberrant the molecules are degraded, and the remainder are polymerized into a conformation that can induce cell stress and inflammation.  These phenomena can lead to disease states such as chronic liver injury, fibrosis, and cirrhosis.  

A1AT Genetic Variants

While it only has a half-life of 3-5 days, the liver produces and secretes 34 mg A1AT/kg body mass on a daily basis in normal physiology. Additionally, it is expressed in neutrophils, macrophages, hepatocytes, pulmonary alveolar, intestine and corneal cells. During acute inflammation, A1AT levels can quadruple in those who otherwise have normal expression of the enzyme.

A1AT Expression

There is evidence to suggest that A1AT has anti-inflammatory properties in different physiological processes:

- A1AT was shown to neutralize plasmin and thrombin in the airway in vitro which activate PAR‐1 receptors that would normally go on to promote TNF‐α
- elevated levels of pro-inflammatory cytokines have been observed in A1AT-deficient individuals
- A1AT were shown to reduce TNF‐α‐TNFR1 by 35% and TNF‐α‐TNFR2 by 50% by binding to TNFR1 and TNFR2 receptors in vitro
- A1AT has been shown to stimulate IL-10 which has anti-inflammatory properties

A1AT in Anti-Inflammatory Processes

Abnormal A1AT activity or deficiency is associated with COPD emphysema.  However, it should be noted that environmental exposures, such as cigarette smoke or poor air quality, are more pertinent risk factors than genetics.  A1AT's protective effects primarily arise from its role in neutrophil regulation.  A1AT enters the lungs via passive diffusion and are taken up by pulmonary epithelial cells via clathrin‐dependent endocytosis.  This process irreversibly inhibits neutrophil elastase (NE).  It functions as a neutrophil chemotaxis modulator by binding to IL-8 which prevents it from interacting with CXCR1.  Additionaly, A1AT inhibits ADAM17 which prompts cell migration during inflammation.   

Learn Before

Related

Learn After