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).