The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in several thousand deaths worldwide in just a few months. Patients who died from Coronavirus disease 2019 (COVID-19) often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. The angiotensin-converting enzyme 2 (ACE2) was identified as a crucial factor that facilitates SARS-CoV2 to bind and enter host cells. To date, no study has assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples of patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients, compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. We also found other genes, such as RAB1A, that can be important for SARS-CoV-2 infection in the lung. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. In fact, epigenetic marks found in ACE2 locus were compatible to with those promoted by KDM5B. Our systems biology approach offers a possible explanation for increase of COVID-19 severity in patients with certain comorbidities.
Discussion
The current diabetes pandemic could be worsening the SARS-CoV-2 pandemic by increasing the comorbidities associated with severe COVID-19. As we did not find lung transcriptome samples from patients with type 2 diabetes, we could not directly test whether ACE2 expression was increased in patients with diabetes, compared to healthy controls. However, our text-mining approach revealed that IL-6 and INS genes were associated with all the diseases we searched. The INS gene encodes the insulin hormone, and insulin is associated with the NAD-dependent histone deacetylase Sirtuin 1 (SIRT1). We found that SIRT1 was up-regulated in the lung of patients with severe COVID-19 comorbidities in 4 out 7 studies (data not shown). Clarke et al have demonstrated that, under conditions of cell energy stress, SIRT1 can epigenetically regulate ACE2. Others too have shown that non-steroidal anti-inflammatory drugs may inhibit the SIRT1 deacetylase activity , which in turn could impact ACE2 expression. The “viral life cycle” pathway that was enriched with up-regulated genes in patients with severe COVID-19 comorbidities contains several genes other than ACE2 that can be potentially important for SARS-CoV-2 cell cycle and invasion/attachment. These include RAB1A gene, whose product promotes the replication of Vaccinia virus [38]. Also, RAB1A is important for Herpes Simplex Virus 1 Secondary Envelopment [39], and is required for assembly of classical swine fever virus particle . It is possible that SARS-CoV-2 utilizes RAB1A as well. The fact that ACE2 gene is located in the X chromosome, and the initial findings showing that older males with comorbidities are more likely to be have severe COVID-19 compared to females , indicate that ACE2 expression in the lung may be sex-biased. Although no significant sexual differences was found in the activity of ACE2 in mouse lung [41], in rats, the levels of ACE2 were dramatically reduced with aging in both genders, but with significantly higher ACE2 expression in old female rats than male. Although the mechanisms by which ACE2 is up-regulated in patients with severe COVID19 comorbidities were not addressed, our analysis may shed some light on the subject. Among the genes whose expression was positively correlated with ACE2, we detected genes associated with epigenetic regulation of gene transcription. For instance, HAT and HDAC modulate chromatin and DNA condensation by changing histone acetylation status, thus permitting gene transcription. This could be happening in lung tissue, facilitating ACE2 expression, as observed during lung cancer and COPD. KDM5B is associated with infection of hepatitis B virus In breast cancer cells, blockage of KDM5 triggers a robust interferon response that results in resistance to infection by DNA and RNA viruses. This finding suggests that KDM5 demethylases are potential targets for preventing SARS-CoV-2 infection. COVID-19 may kill between 5.6% and 15.2% of people infected with SARS-CoV-2. Drug treatments that lower this mortality rate may save many thousands of lives. Our systems biology approach offers putative gene targets for treating and preventing severe COVID-19 cases.
Reference & source information: https://www.medrxiv.org/
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