Augmented ACE2 Activity, Cytokine Profiles, and Differential Lipid Mediators Reveal Increased Susceptibility Towards SARS-CoV2 Infection in Smokers

Abstract

Rationale: The recent pandemic of COVID-19 is characterized by pulmonary symptoms leading to acute lung injury and lung remodeling in the airway and alveolar regions of the lungs, which eventually culminates to lung pneumonia. Tobacco smoking has been known to cause lung oxidative stress and inflammatory responses, rendering smokers susceptible to infections. However, the progression of lung injury based on COVID19 susceptibility and severity amongst smokers is not known. Considering this, we intended to study the expression and activity of COVID19 receptor, ACE2, cytokine/chemokine production, and lipid mediators (lipidomics) amongst COVID19 patients with and without a smoking history. Methods: We collected serum from COVID19 positive, COVID19 negative and COVID19 recovered patients with and without a smoking history and studied the cytokine production and ACE2 activity by Luminex multiplex and enzymatic assays, respectively. We further performed LC/MS (eicosanoids or oxylipid panel) on the serum samples to study the changes in the serum lipids from COVID-19 positive and recovered patients. Results: Our results showed a significant upregulation in the production of pro-inflammatory cytokines like MCP-1(10-fold, p<0.01), IL-17 (∼10-fold, p=0.059), IL-7 (2-fold, p<0.05), IL-13 (2-fold, p<0.05), and MIP-1β (∼1.2 fold, p<0.05) in COVID19 positive patients as compared to healthy controls. Interestingly, smoking history resulted in further augmentation of the release of MCP-1 (3-4-fold, p<0.05), IFN-γ (2-3 fold, p=0.086) and Eotaxin (2-3-fold, p<0.05). The enzymatic activity for ACE2 was also found to be increased in the blood serum from COVID-19 positive patients as compared to COVID-19 recovered individuals. ACE2 is a transmembrane protein that is known to be over-expressed on the airway epithelium of smokers. In fact, on comparing the ACE2 activity amongst COVID19 patients based on their smoking history, we observed a 7-10% increase in the ACE2 activity amongst smokers. Lipid mediators profile revealed distinct signature among the positive versus recovered subjects in 12-HETE, 8(9)-EET and 11(12)-EET levels. However, we did not find any changes in the levels of any lipid mediators based on the smoking history of the patients. Conclusion: Overall, our results point towards an augmentation of cytokine/chemokine production and ACE2 activity along with differential profile of lipid mediators amongst COVID19 patients with a smoking history, thus pointing towards the possibility of a more severe and rapid worsening of the disease symptoms amongst these individuals.