key: cord-0722554-aul994nn authors: Shimi, Ghazaleh; Zand, Hamid title: Association of alpha-1-antitrypsin deficiency with vitamin D status: who is most at risk of getting severe COVID-19? date: 2021-03-19 journal: Inflamm Res DOI: 10.1007/s00011-021-01456-z sha: 0f6bb9d2f322aff7f26c2f2aac4c677fa761cb84 doc_id: 722554 cord_uid: aul994nn INTRODUCTION: Coronavirus disease 2019 (COVID-19), a new disease that we do not know yet how to treat, is rapidly evolving and has forced us to stay indoors. Surprisingly, a broad range of symptoms has been reported since COVID-19 emergence. Individual variations in susceptibility to SARS-CoV-2 can be due to non-genetic and genetic factors. Alpha-1-antitrypsin deficiency (AATD) is an inherited condition that is associated with an increased risk of liver and lung diseases which may increase susceptibility to COVID-19 infection. At the same time, there could be a possibility of developing non-hereditary AATD. DISCUSSION: In addition to some evidence showing the role of vitamin D deficiency in COVID-19 pathology, it has been recognized that there is a biological link between AAT and vitamin D. Therefore, here we offer a new perspective that lower vitamin D levels in COVID-19 patients can cause acquired AATD that provide a condition with more disease severity and a higher risk of death. As a consequence, COVID-19 individuals with vitamin D deficiency may have a higher risk of morbidity and mortality. CONCLUSION: Therefore, early vitamin D and AAT assessments and optimal interventions could be helpful to prevent severe COVID-19 outcomes. In December 2019, coronavirus disease 2019 (COVID- 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared in China and led to a rapidly progressing pandemic. Following that, communications were declined and people were quarantined in their homes. Strangely and sadly enough, responses and reactions to COVID-19 appear to be widely different, ranging from asymptomatic or mild to severe conditions and death, among different people and regions. Non-genetic factors, including age, comorbid conditions such as cancer and cardiovascular disorders, and environmental risk factors like air pollution, may confer differential susceptibility to SARS-CoV-2 infection. Similarly, host genetic factors can influence the severity of the disease. Therefore, understanding the non-genetic/ Among genetic factors, one candidate gene might be SERPINA1 which encodes the alpha-1-antitrypsin (AAT) protein. AAT is an acute-phase protein that is mainly produced by liver cells and subsequently secreted into the plasma but is also secreted to a lesser extent by monocytes, macrophages, pulmonary alveolar cells, and intestinal epithelium [4] . In addition to its anti-proteinase function and inhibition of neutrophil proteinases including neutrophil elastase, cathepsin G, and proteinase 3; AAT has several known non-proteinase effects including anti-inflammatory and immunomodulatory characteristics and antimicrobial/ antiviral properties [5, 6] . Hereditary AATD is characterized by decreased serum level or abnormal AAT functions and is also associated with an increased risk of liver and lung diseases [7] which may increase susceptibility to COVID-19 infection. Considering the information provided, the article by Shapira et al. reported that frequencies of AATD alleles were positively correlated with the COVID-19 fatality rate [8] . Moreover, since the Lombardia region in Italy with 37.8% of COVID-19 casualties, also had 47% of all AATD cases, Vianello and Braccioni suggested that AATD may explain the high mortality rate of COVID-19 [7] . Notably, these findings could be due to the fact that TMPRSS2 (transmembrane serine protease 2) which promotes COVID-19 cell entry, cannot be suppressed by AAT in AATD patients. Besides, AAT improves inflammatory conditions by reducing ADAM17 (a disintegrin and metalloproteinase-17) activity which is responsible for the breakdown of ACE2 (angiotensin-converting enzyme 2) and the imbalance of the renin-angiotensin-aldosterone system (RAS) [7, 9] . Remarkably, Ray et al. demonstrated that while any underlying genetic reason for the observed AATD had been ruled out in their tropical pulmonary eosinophilia subjects, acquired AATD existed as a result of the chronic inflammation and oxidative stress. Ray et al., also, had ruled out the possibility of any intestinal AAT loss in their worm-infested pulmonary eosinophilia subjects [10] . Accordingly, it could be possible to assume non-hereditary AATD development in COVID-19 patients. Thus, in the following section, this article will dive into a way that how AATD acquisition can be developed by COVID-19 patients? AATD and vitamin D deficiency are tightly linked to inflammation and autoimmunity [11, 12] . Both AAT and vitamin D have strong immune-modulating roles in the airways environment [13] . A study by Dimeloe et al. reported that vitamin D active form (1,25(OH)2D3) causes CD4 + T cells to secrete AAT, and AAT, via direct interaction with complement C3a, promotes IL-10 (interleukin 10) secretion; meaning that AAT is essential for 1,25(OH)2D3 to induce IL-10. Dimeloe et al., also, stated that 1,25(OH)2D3 failed to enhance IL-10 transcription in CD4 + T cells from hereditary AATD individuals (PiZZ) compared to the healthy subjects [13] . This implies that 1,25(OH)2D3 is a key upstream regulator in this antiinflammatory axis in CD4 + T cells. At the same time, Lindley et al.'s study on type 2 diabetic patients showed that low circulating levels of AAT were positively associated with lower 25(OH)VD levels, suggesting that 25(OH)VD deficiency may predispose type 2 diabetic patients to AATD which may cause a higher incidence of COPD (chronic obstructive pulmonary disease) in diabetes [14] . Moreover, Crane-Godreau et al.'s study on mice exposed to cigarette smoke reported that vitamin D deficiency causes a significantly lower AAT expression in the lungs and emphysema [15] . In the meantime, vitamin D and COVID-19, both, have the same target which is RAS and the immune system. Luckily, vitamin D regulates the RAS and avoids bradykinin accumulation, and has a strong protective effect against acute lung injury and acute respiratory distress syndrome (ARDS). Conversely, COVID-19 kills through bradykinin storm, along with the cytokine storm. It is a well-known fact that vitamin D decreases remarkably in severely ill patients with COVID-19 [16] [17] [18] . Several studies have reported the possible link between vitamin D concentrations and COVID-19 severity and fatality [19] [20] [21] [22] . However, not much is known about the potential role of vitamin D in preventing and treating COVID-19 infection. Yet, here we suggested that vitamin D deficient COVID-19 individuals may acquire AATD, and that is what makes the illness more severe once the patients are infected. In conclusion, lower vitamin D levels in COVID-19 patients may cause acquired AATD that provides a condition with more disease severity and a higher risk of death. Further investigations are required to demonstrate the association between AAT levels and vitamin D status. Notably, vitamin D and AAT assessments would be essential to detect deficient persons and optimal interventions could be helpful to prevent severe COVID-19 outcomes. Author contributions Conceptualization: GS, HZ; Writing-original draft preparation: GS; Writing-review and editing: GS, HZ; Supervision: HZ. Funding No funds, grants, or other support was received. The authors have no conflict of interest to declare that are relevant to the content of this article. Deciphering the role of host genetics in susceptibility to severe COVID-19. Front Immunol Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis Alpha 1-antitrypsin deficiency: a disorder of proteostasis-mediated protein folding and trafficking pathways Neutrophil modulation in alpha-1 antitrypsin deficiency Alpha-1 antitrypsin: it's role in health and disease Geographical overlap between alpha-1 antitrypsin deficiency and COVID-19 infection in Italy: Casual or causal? 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