ACE 2, cytokines and co-morbidity in COVID-19 disease
The genome sequence analysis of human pathogenic SARS-CoV-2 is 80% identical to SARS-CoV and enter the host cell through lungs angiotensin-converting enzyme 2 (ACE 2) receptor and triggers a strong immune response which leads to a cytokine storm, generates an inflammatory response, damage the pulmonary tissue thereby induces acute respiratory distress syndrome (ARDS) (Li, Liu, Yu, Tang & Tang, 2020). Evidences showed that cytokines storm play an essential role in the pathogenetic mechanisms of multi-organ failure (Aikawa, 1996; Ura, Hirata, Yamaguchi, Katsuramaki & Denno, 1998; Wang & Ma, 2008). The overproduction of pro-inflammatory cytokines results in systemic inflammation, activation of transcription factor NF-kappaB that regulates expression of various pro-inflammatory genes and downregulates the cell-mediated immunity which impairs the balance between T helper 1 and T helper 2 cytokines and induces multi-organ damage (Ura, Hirata, Yamaguchi, Katsuramaki & Denno, 1998). Further, cytokines directly bind to the transmembrane tyrosine kinase receptor which does not have intrinsic activity and this induces dimerization of the receptor, activates the Janus kinase (JAK) and signal transducer-activator of transcription (STAT) signalling pathway thereby modulating the inflammatory and immune response (Ivashkiv, 2000; Kong, Horiguchi, Mori & Gao, 2012). Likewise, SARS-CoV-2 after interacting with ACE 2 induces the massive production of pro-inflammatory cytokines leading to cytokine storm and can increase the risk of multi-organ failure (Jose & Manuel, 2020).
The reason for multi-organ damage by SARS-CoV-2 infection in co-morbid condition is the profuse presence of ACE 2 on the intestine, heart, kidney, liver, pancreas, cerebral neurons, vascular endothelial cells, testes, immune cells, uterus, placenta and fetus (Hamming, Timens, Bulthuis, Lely, Navis & van Goor, 2004a; Roca-Ho, Riera, Palau, Pascual & Soler, 2017). Evidence is very alarming that there is an increased mortality rate in older COVID-19 patients with preexisting diseases such as hypertension which is the most common reason for the comorbidity, followed by other cardiovascular diseases, diabetes, chronic kidney disease, cerebrovascular disease, chronic obstructive pulmonary disease and lastly cancer (Hussain, Bhowmik & do Vale Moreira, 2020; Valencia, 2020). A gender-wise comparison shows that most of the COVID-19 patients were older males. Low incidences of SARS-CoV-2 infection in females might be explained by the presence of a high level of the protective hormone estrogen and progesterone, however, the exact reason is not clear (Chen et al., 2020b; Hanff, Harhay, Brown, Cohen & Mohareb, 2020). Further, patients with diabetes are often suffering from coronary artery disease, high blood pressure, coagulant-anticoagulant imbalance, renal disorder and co-existence of multiple diseases compromise the immune function and this may be another reason for the increased incidence of SARS-CoV-2 infection (Ferlita et al., 2019; Sardu, De Lucia, Wallner & Santulli, 2019). Some evidence shows that increased incidence of transmission of infectious diseases such as H1N1, influenza, staphylococcus and tuberculosis in patients with diabetes mellitus may be due to altered immune functions (Casqueiro, Casqueiro & Alves, 2012; Klekotka, Mizgała & Król, 2015). Moreover, SARS-CoV interacts with pancreatic ACE 2, damages the islet and this may lead to altered insulin secretion (Yang, Lin, Ji & Guo, 2010). In addition, diabetes, hypertension, smoking, aging and preeclampsia upregulates the ACE 2 expression which is a pivotal interacting site for SARS-CoV-2 (Leung et al., 2020; Levy, Yagil, Bursztyn, Barkalifa, Scharf & Yagil, 2008; Roca-Ho, Riera, Palau, Pascual & Soler, 2017).