key: cord-0812559-9ucrgpib
authors: KaviyarasiRenu; Prasanna, Pureti Lakshmi; Abilash, V.G.
title: Coronaviruses pathogenesis, comorbidities and multi-organ damage – A review
date: 2020-05-22
journal: Life Sci
DOI: 10.1016/j.lfs.2020.117839
sha: a919028b77011921f87b1e11d937cf198c0a708f
doc_id: 812559
cord_uid: 9ucrgpib

Human coronaviruses, especially COVID-19, is an emerging pandemic infectious disease with high morbidity and mortality. Coronaviruses are associated with comorbidities, along with the symptoms of it. SARS-CoV-2 is one of the highly pathogenic coronaviruses that causes a high death rate compared to the SARS-CoV and MERS. In this review, we focused on the mechanism of coronavirus with comorbidities and impairment in multi-organ function. The main dysfunction upon coronavirus infection is damage to alveolar and acute respiratory failure. It is associated with the other organ damage such as cardiovascular risk via an increased level of hypertension through ACE2, gastrointestinal dysfunction, chronic kidney disease, diabetes mellitus, liver dysfunction, lung injury, CNS risk, ocular risks such as chemosis, conjunctivitis, and conjunctival hyperemia, cancer risk, venous thromboembolism, tuberculosis, aging, and cardiovascular dysfunction and reproductive risk. Along with this, we have discussed the immunopathology and coronaviruses at a molecular level and therapeutic approaches for the coronavirus infection. The comorbidities and multi-organ failure of COVID-19 have been explained at a molecular level along with the base of the SARS-CoV and MERS-CoV. This review would help us to understand the comorbidities associated with the coronaviruses with multi-organ damage.

J o u r n a l P r e -p r o o f changes include vascular edema, vascular injury, including small vessel vasculitis [49] , desquamation of squamous metaplasia, and epithelial cells [50] , pulmonary infarcts and vascular fibrin thrombi [51] .BOOP-like lesions such as the proliferation of fiber granulation tissue in alveolar spaces located subpleural and small airways. Also, the severity of the clinical manifestations depends on the stage of disease or onset of the disease which has been classified into three stages., edema, alveolar hemorrhage, fibrin exudation in alveolar spaces, hyaline membrane formation, and extreme bronchiolar injury indicate the acute phase, the first phase during the infection [50] (represented in table 1).

Secondly, the proliferative phase characterized by cellular fibromyxoid-organizing exudates, widening of septae, and pneumocyte hyperplasia [52] . Formation of alveolar and septal fibrosis, where the severity of the fibrosis depends on the onset and duration of the disease [49, 53] .

Coronaviruses share a common inclination in infecting the central nervous system in some cases. A case was reported where a 39 years old doctor who got infected with SARS-CoV exhibited usual symptoms and was hospitalized. After hospitalization, he was presented with eyesight problems and later started exhibiting central nervous system symptoms such as delirium and restlessness. After a month, he passed away. When his brain tissue was examined, this revealed the presence of SARS-CoV virus. The doctors reported that he might have got infected while treating the patients, and also the chemotactic attraction of immune cells by the infected brain cells might have injured the brain more than that of the viral infection. The chemotactic attraction was characterized by the presence of a chemokine called monokine induced by gamma interferon (Mig) found in the patient's brain and the bloodstream [54] (represented in table 1).

J o u r n a l P r e -p r o o f interferons (IFN-α/β); upregulation of the pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor (TNF) and upregulation of the inflammatory cytokines such as C-C Motif Chemokine Ligand 2 (CCL2), C-C Motif Chemokine Ligand 3 (CCL3), C-C Motif Chemokine Ligand 5 (CCL5) and C-X-C motif chemokine 10(CXCL10) [55, 56] . Macrophage infected with the SARS-CoV showed an elevated level of the other pro-inflammatory cytokines and IFN. Also, the epithelial cells infected with the SARS-CoV have an enhanced CCL2, CCL3, CCL5, and CXCL10 [56, 57] .

Along with the chemokines and pro-inflammatory cytokine, there is an elevated level of the IFN inclusive of IFN-α and IFN-γ, stimulatory genes of IFN include CCL-2 and CXCL-10. There is an exacerbation of the IFN, chemokines such as TNF, IFN-γ, IL-6 and CCL5, pro-inflammatory cytokines and stimulatory genes of interferon such as an interferon-induced protein with tetratricopeptide repeats 1) IFIT1, radical S-adenosyl methionine domain containing 2 (RSAD2) and CXCL10 in the TIR-domain-containing adapter-inducing interferon-β (TRIF) and toll-like receptors 3 (TLR3) deficient mice [58] . The deregulation of the cytokine or chemokine response causes the cytokine storm, leading to the immunopathological changes and the SARS-CoV infection.

In Saudi Arabia, in June 2012, a new virus outbreak took place, which caused fever, dry cough, and shortness of breath resulting in respiratory illness [59] . The disease spreads from person to person through direct contact with the infected person. It is believed that the MERS-CoV had originated from bats, and dromedary camels are intermediate hosts for transmitting the disease to J o u r n a l P r e -p r o o f 13 

Metabolic disorder related conditions, for example, hypertension, diabetes, obesity, and cardiovascular diseases, together with their inclining conditions, can be connected etiologically to the pathogenesis of MERS-CoV. These conditions act to decline the innate immune system of the host, thereby the inability of the host to fight against the pathogenesis of MERS-CoV. A study conducted on 637 MERS-CoV patients revealed that 15% of them have diabetes, 16% of them are obese, 50% of them had hypertension, and 30% are predisposed to cardiovascular diseases [65] . A 57-year-old diabetic and the hypertensive patient exhibited myocardial ischemia besides edema in the pulmonary tract, elevated troponin levels which returned to normal after 48hrs, a chronic severe 3-vessel disease with no acute vessel closure characterized by coronary angiography. Later, he didn't respond and became hypotensive with facial paralysis on the left side [66] .

The patients infected by MERS-CoV were also presented with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels above normal. Besides the elevated liver enzymes, the albumin levels were decreased, which serves as an indicator of the severity of the disease [67 -69] . The MERS-CoV enters the host cell through the DPP-4 receptor and spreads the infection [70] .The liver is the main organ that expresses high levels of Dipeptidyl peptidase 4 (DPP-4) [71] .This was experimentally proved by infecting the transgenic mice expressing hDPP4 with MERS-CoV which indicated that the liver injury had taken place on the 5 th day of the infection as evidenced by the pathological manifestations such as disintegrated death of hepatocytes in the hepatic sinus, penetration of large amounts of activated macrophages and Kupffer cells. The changes related to fat metabolism were observed on the 9 th day of infection, and the liver cell necrosis was quite less [72] (represented in table 1 ).

The histopathological findings of the hepatic tissue during MERS-CoV infection include infiltration of lobular lymphocytes, mild cellular hydropic degeneration in hepatic parenchyma, and mild portal tract [73, 74] . During the acute phase of infection, the levels of pro-inflammatory The patient experienced multiple cardiac arrests, severe shock, and acute kidney injury and eventually expired. Forty-five-year-old patients with acute kidney injury, diabetes, and hypertension were tested positive for MERS-CoV, and CT scan findings revealed no acute abnormalities but exhibited similar findings consistent with encephalitis. The patient exhibited lymphocytopenia and was tested negative after a few days [66] .

Like the SARS-CoV, MERS also has an infection in the airway epithelial cells, which enhances the level of pro-inflammatory cytokines and IFN in a delayed manner [81] . Even in the cells of THP-1, macrophage-derived from the human peripheral blood, dendritic cells showed an elevated level of the chemokines such as CCL3, CCL2, IL-2, IL-8, and CCL-5 and pro-inflammatory cytokines in a delayed manner during MERS-CoV infection [82, 83] . The high level of the pro-inflammatory cytokine and chemokine associated with the enhanced level of the monocyte, neutrophil numbers in both the lung and peripheral blood, which leads to immune damage [84] .

ACE2 plays a vital role in the cardiovascular system and is mainly involved in the functioning of the heart and development of hypertension and type II diabetes. Since ACE2 is the main target for J o u r n a l P r e -p r o o f severity of the viral infection is higher in patients with comorbidities than those infected only by the virus without any predisposed health issue [85] .

The interaction of the SARS-CoV-2 with ACE2 triggers a signal, which might be the reason to develop heart injury through the immune response triggered by T-helper cells creating a cytokine response. The SARS-CoV-2 has a structural similarity with that of SARS-CoV. SARS-CoV caused severe cardiovascular damage during its pandemic period. Therefore, it is essential to investigate SARS-CoV-2 treatment options and ensure a cardio-protective effect. The age and the predisposition of the acute coronary syndrome are the two critical factors which need to be considered in patients affected with COVID-19 [85] .

Since the ACE2 is highly expressed in pericytes, the patients infected with SARS-CoV-2 and predisposed with cardiac failure are more susceptible to develop severe cardiac problems [86] . The usage of mineralocorticoids receptor blocker can attenuates oxidative stress, reduces the level of ACE with the augmented production of the angiotensin 1-7 and attenuates the angiotensin II generation and increases the activity of ACE2 The antagonist of angiotensin II type 1 receptor, have modulates the profilin-1 expression and ACE2 [87] .The selective of the angiotensin II activity or synthesis mediated the augmented level of ACE2 expression and its activity in cardiac. Still, the combination of the lisinopril and losartan increases the activity of ACE2 but not ACE2 mRNA. The inhibition of ACE results in reduced formation of angiotensin II and metabolism of angiotensin 1-7, the angiotensin II type 1 receptor antagonist increases the metabolism of angiotensin II via ACE2 [88] . SARS-CoV 2 enters into the cell via the ACE2 receptor; this causes the decreased level of the ACE2 due to the binding of the spike protein to the ACE2 and no changes in ACE. This process causes the virus's entry, replicates it, and causes tissue injury via decreasing anti-atrophy, anti0-fibrosis, antiinflammation, anti-oxidant, and vasodilation. On the other hand, the angiotensin II type 1 receptor causes pro-atrophy, pro-fibrosis, pro-inflammation, pro-oxidant, severe myocardial remodeling, vasoconstriction and vascular permeability which leads to tissue injury [89] (represented in table 1).

Therefore, the use of ACEi, ARBs, and mineralocorticoids has shown to have an impact on the cardiac patients affected by COVID-19, but the exact mechanism behind it is not clear. Aliskiren, J o u r n a l P r e -p r o o f a direct inhibitor of renin, resulted in reduced expression of ACE2 besides reducing the blood pressure that has been elucidated in diabetic nephropathy animal models [90] . Therefore, renin blockers, especially aliskiren, need to be further investigated as a treatment option for COVID-19 patients with comorbidities [91] .

The ACE2 is also highly expressed in the small intestine and large intestine of the gastrointestinal tract. The S protein present on the envelope of the SARS-CoV-2 ensures higher binding affinity, thereby mediating the entry of the virus into the host cell. The presence of SARS-CoV-2 in the gastrointestinal tract was confirmed by nucleocapsid staining of the virus. The virus was found to be visualized in the cytoplasm of epithelia of duodenum and rectum [92] (represented in table 1). Apart from the pulmonary infection, the COVID-19 affected patients also exhibited vomiting, abdominal pain, and diarrhea, which was first reported in a 35 years old man from the United States. He was presented with nausea and diarrhea on 2 nd day of the infection and was hospitalized. Stools examination revealed the presence of SARS-CoV-2 RNA, which was confirmed by using reverse transcriptase-polymerase chain reaction (RT-PCR) on day 7 of infection [93] .Out of 171 COVID-19 affected children, 6.4% of them have shown vomiting, and 8.8% of them and 3 out of ten affected children have shown diarrhea as symptoms [94] . Also, previously there were two COVID-19 young cases reported with vomiting and diarrhea.

In China, from 552 hospitals, 1099 cases were reported, of which 3.8% and 5% were diagnosed with diarrhea and vomiting as symptoms [95] . According to another report, out of 140 COVID-19 patients from Wuhan, 39.6% exhibited gastrointestinal symptoms apart from 5% exhibiting vomiting, 12.9% exhibiting diarrhea, and 17.3% exhibiting nausea [96] . It was reported that 17 patients had shown a negative result when tested using pulmonary samples, but when tested using rectal swabs have shown to have a positive result [96] .

Similarly, 8 out of 10 children affected by SARS-CoV-2 had shown dual results, negative results when tested by nasopharyngeal samples, and positive results when tested using a rectal swab J o u r n a l P r e -p r o o f 18 [97] . The percentage of patients exhibiting nausea, vomiting, and diarrhea as symptoms vary between the cohort groups, whereas, in the case of certain groups, these symptoms contributed very few percent. In contrast, in the case of the other groups, a high percentage of these gastrointestinal symptoms have been recorded.

It is suspected that whether the patients with predisposed kidney issues or COVID-19 induced acute kidney injury is fatal to the affected patients. In an article posted on March 19 by HospiMedica International staff writers, it was mentioned that patients affected by COVID-19 developed proteinuria estimated by the elevated levels of albumin in urine were diagnosed in the initial stages of infection. The majority of the affected members, i.e., 34% out of 59 patients, developed proteinuria where the elevated albumin levels serve as a biomarker for kidney damage, and 63% of the patients exhibited proteinuria and hematuria characterized by the presence of blood in the urine. In another study conducted on 710 patients hospitalized due to COVID-19. The impairment in the functioning of the kidney was observed in 27% of the 59 patients and 66% of the corona infected patients. In a later study conducted on COVID-19 affected patients from 710 hospitals, 26.7% exhibited only hematuria, and 44% exhibited proteinuria and hematuria. The impaired kidney function was found in 15% of the study population [98] .

According to an article published by Wang L and his colleagues reported that out of 116 COVID-19 positive cases from Renmin Hospital of Wuhan University, out of whom 111 didn't have any kidney issues in their history and the remaining five patients had chronic kidney disease (CDK).

Also, out of the 111 patients, only 10.8% of the patients exhibited a slight increase in creatine or blood urea nitrogen levels, and 7.2% of the patients had shown a minute raise in the albuminuria levels. None of the patients out of 111 didn't exhibit any acute kidney injury (AKI) after the COVID-19 infection.The remaining five patients who were already undergoing continuous renal replacement therapy (CRRT) also didn't show any fatal effects after COVID-19 infection confirmed by diagnosing the renal indicators [99] . Out of 701 patients, 2% of the patients were found to have CKD, and the average lymphocytic number was found to be reduced than the normal. High sensitivity C-reactive J o u r n a l P r e -p r o o f protein levels were significantly increased. In patients reported with high levels of serum, creatine indicated high levels of serum lactose dehydrogenase. Among hospitalized patients, patients with high levels of serum creatine were mostly old and male sex. Also, they exhibited lower platelet and lymphocytic count and elevated leukocytic count. The patients with elevated procalcitonin also exhibited elevated levels of aspartate aminotransferase and lactate dehydrogenase. Acute kidney injury was significantly higher in those patients with high serum creatine levels. AKI eventually results in mortality [100] (represented in table 1). Therefore, advanced identification of kidney diseases in patients affected by COVID-19 may help the clinicians to reduce the mortality rate due to comorbidities such as chronic kidney disease, acute kidney injury, proteinuria, and hematuria.

Patients with diabetes mellitus exhibit high levels of ACE2, and treatment with the inhibitors of ACE and ARBs augments the expression of ACE2. Diabetes condition may lead to the suspicion that the excessive expression of ACE2 aids the entry of SARS-CoV-2 into the host cells resulting in COVID-19. Since diabetes mellitus and hypertension conditions are treated, ACE2 increasing drugs are having a severe risk of COVID-19 [10] .

Simultaneously, the elevated expression of ACE2 ensures the entry of the SARS-CoV-2, attaching to the ACE2 enzyme with the help of S protein present on its envelope's surface. There forth, it became controversial whether COVID-19 affected patients who are predisposed with diabetes mellitus should be resumed with their treatment with ACEi and ARBs or not. Also, if the medication is abruptly ceased, there are chances that the patient may die due to hypertension instead of COVID-19. For this reason, it has been suggested that there is no need to stop the medication of a diabetic patient even though if he is affected by COVID-19 because there is no scientific evidence available conducted on human subjects regarding whether to use ACEi and ARBs [10] .

The SARS-CoV-2 infection has shown to increase the levels of ALT, AST, and bilirubin levels, indicating injury to the hepatic tissue [9, 95, 101, 102] . Apart from these liver serum enzymes SARS-CoV and SARS-CoV-2 share the similarity in making an entry into the host cell through the ACE2 receptor. In addition to the type 2 cells in the lungs, both the bile duct cells and hepatocytes also express ACE2, which might be the reason that liver injury occurs during SARS-CoV-2 infection [103] .The bile duct epithelial cells are involved in immune responses and the regeneration of the hepatocytes [104] . Besides possessing a high number of ACE2 on its surface, bile duct cells are more prone to the SARS-CoV-2 infection resulting in liver injury, which indicates that the hepatocytes are not directly involved in the hepatic injury [37] . The histopathological manifestations of SARS-CoV-2 infected patients revealed mild lobular and portal activity and restrained microvascular steatosis [105] .The degree of liver damage is directly proportional to the severity of the SARS-CoV-2 infection. Still, the reason for the liver injury remains elusive. A recent study reported that the use of anti-viral medication lopinavir might result in hepatic damage [102] .Therefore, whether the liver injury is due to the virus entry or due to the drugs used as anti-viral medication needs to be elucidated.

It was possible to study the lung pathology of COVID-19 patients diagnosed with COVID-19 retrospectively after undergoing lung lobectomy surgery for adenocarcinoma. Also, the patients didn't present pneumonia at the time of surgery, indicating the initial stages of COVID-19. A female patient who was 80 years old was hospitalized due to an irregularly shaped solid nodule in the right middle lobe. On a postoperative day 1, a CT scan was performed, which indicated a few clinical manifestations. Later, the patient was presented with increased leucocytes, decreased lymphocytic count, chest tightness, wheezing, dry cough, and difficulty in breathing. Later findings confirmed that SARS-CoV-2 infected her from a patient in the same room who was already affected. Another patient who was 73 years old and had a medical history of hypertension from 20 years who underwent J o u r n a l P r e -p r o o f surgery for adenocarcinoma was discharged on the 6 th -day post-operation. On postoperative day 9, the patient exhibited chest tightness, muscle pain, dry cough, and decreased lymphocytic count. His CTscan findings revealed for viral pneumonia, and he was also tested positive for the 20189-nC0V test.

He was admitted to the infectious disease ward. After, 20 days he was discharged as he recovered.

Histopathological findings showed focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, edema, multinucleated giant cells, protruding hyaline membranes, and proteinaceous exudates [106] (represented in table 1 On the other hand, the T-cells are having four types of it, such as Th1, Th2, Th17 (inflammatory), and anti-inflammatory Tregs. These Th2 cells generate IL-4 cells. The compound which can block the Th1 (Boost immune system) tends to augments the level of the Th2 (antiinflammatory response). IL-4 triggers the Th2 cells and obstructs the Th1 response. This Th2 helps to repair form tissue dysfunction and another type of malfunction. It is found to be good that the J o u r n a l P r e -p r o o f cancer patients than non-cancer COVID-19 affected patients. Also, COVID-19 patients with cancer exhibited a severe chain of symptoms than those without a history of cancer. Also, patients with lung cancer did not exhibit severe symptoms when compared to those with other types of cancers [122] .

In a retrospective study conducted among 1276 patients, 28 patients who have cancer were selected for the study. The mean age group people belonged to the elderly category, and 60.7% of them were males. Lung cancer was the most frequent type, followed by oesophageal and breast cancers among cancer affected patients. 10 out of 28 patients were presented with IV stage cancer. and ARDS [123] . Therefore, more focus should be laid on the research for medication and treatment options for COVID-19 affected cancer patients. More studies are required to determine the exact mechanism behind cancer and SARS-CoV-2.

A study was conducted in February 2020, Shenyang, China, which involved 36 COVID-19 positive patients and was classified based on the severity of the symptoms as mild and critical. The results of these patients were compared with that of the patients affected by pneumonia caused by Mycobacterium tuberculosis from Shenyang chest hospital. The study was conducted to determine which one caused severe pneumonia, either the viral or the bacterial strain. Then the severity of tuberculosis was compared between the mild and severe COVID-19 cases and confirmed that tuberculosis due to mycobacterial strain affected patients are more susceptible to COVID-19 and J o u r n a l P r e -p r o o f 26 from the infection the same as that of those without HIV. There is no evidence on whether HIV patients are more susceptible to COVID-19 infection [125] .

The COVID-19 associated TB is found in 94 th day of the nonexistence of public health interventions and 138 th day in the occurrence of interventions. This occurs at the peak of an outbreak where the implementation of the intervention, out of it 11,066, is with the presence of interventions.

27,968 COVID-19 cases found in the absence of interventions, out of it 14,823, are with no interventions. This scenario shows that there is a need to take preventive measures of TB associated with COVID-19 patients. They need a prior diagnosis and proper management [126] . The main reasons for mortality are age, sex, and other co-morbid factors such as diabetes, cardiovascular diseases, and renal diseases are the main reasons for mortality. J o u r n a l P r e -p r o o f monophosphate dehydrogenase enzyme [131] [132] [133] . 5' triphosphate metabolite of ribavirin, which inhibits the virus's polymerase activity, viral capping inhibition, and induces lethal mutagenesis in the RNA genome of the virus, resulting in the anti-viral effect of ribavirin [134] .The route of drug administration includes aerosol, oral, and intravenous. This drug is used to treat SARS-CoV infection.

It has resulted in severe adverse effects, including anemia in about 27-59% of tested patients, which further led to dreadful outcomes such as tissue hypoxia [135] [136] [137] [138] .Also, it elevated the levels of transaminases and resulted in hypocalcemia, hypomagnesemia, developed the risk of teratogenicity and bradycardia [139] .

Lopinavir and ritonavir, protease inhibitors are used in combination to treat SARS-CoVas the drugs were effective against the virus [135] ; whereas, this combination is usually used in HIV treatment. The ritonavir inhibits the CYP3A metabolism of lopinavir, thereby making the drug available for a longer time by increasing the serum concentration. The lopinavir and ritonavir exhibited very few adverse effects, and beneficial outcomes of this combination of drugs include decreased viral load, increase in the lymphocytic count, and a reduced need for ‗‗rescue'' pulse steroid doses [140] . Viral infection activates the immune system. The corticosteroids have been used to eliminate and inhibit the cytokine storm and further, which has been initiated by the virus. The viral infection affects a cascade of the immune system, which leads to the production of cytokines such as tumor necrosis factor, IL-1, IL-6, and interferon-gamma, which results in injury to the tissue [141, 142] .

Another possible treatment is the usage of convalescent plasma where the plasma from a recovered patient is transferred to an infected patient, which results in the adaptive immune response against the infectious agent since the recovered patients have antibodies against the infectious agent.

The convalescent plasma had been shown as a better treatment option for SARS-CoV affected patients. This treatment reduced the mortality rate, improved the medical condition of the patient [143- J o u r n a l P r e -p r o o f was also administered at a dosage of 500 mg, the patients treated with a combination of hydroxychloroquine and azithromycin exhibited 100% cure and tested negative for PCR results;

whereas, the patients treated with hydroxychloroquine alone exhibited only 57.1% success rate. This combinational therapy might be an approachable way to cure COVID-19 and needs to be tested over a large sample size [147] . Another drug combination, which includeslopinavir and ritonavir, had no invitro evidence for COVID-19. Also, the clinical trials are being carried out on malarial drugs chloroquine and hydroxychloroquine (represented in table 2). Some scientists say that these drugs are not recommendable against SARS-CoV-2. Since there are no scientific proofs available and it might be harmful, leading to heart arrhythmia.

The SARS-CoV-2 mild/moderately affected patients exhibit symptoms such as dry cough, fever, and shortness of breath. In the case of severely affected individuals, hyperactivation of immune cells leads to the cytokine storm, which is created upon SARS-CoV-2 infection, resulting in the inflammation at the targeted tissues. Therefore, inhibiting the pro-inflammatory candidates might be a potential therapeutic option to treat COVID-19 [148] . Anti-TNF therapy was approved and has been utilized for 20 years as a promising option to treat autoimmune diseases such as ankylosing spondylitis, rheumatoid arthritis, and inflammatory bowel disease [149] . TNF is the key enhancer of inflammation and also present in the blood of COVID-19 severely affected patients [150] . Therefore, prescribing anti-TNF therapy may help to prevent the aggression of the infection. It has been reported that patients with inflammatory bowel disease contracted with COVID-19. One hundred sixteen patients were on anti-TNF therapy, of whom 99 recovered, and only one patient died. Therefore, the usage of anti-TNF therapy may stand as a promising therapy to prevent the progression of the viral infection by inhibiting the key pro-inflammatory cytokine TNF [148] .

ACE2 is required for the degradation of Ang II to Ang (1-7), reducing the blood pressure through vasodilation. ACE2 exists as both membranous forms, which are found to be anchored to the J o u r n a l P r e -p r o o f plasma membrane and the soluble form, circulating in the bloodstream but at a lower proportion [151, 152] . Besides serving as an entry point for SARS-CoV-2, the higher levels of ACE2 are required by the hypertension patient to reduce the blood pressure. Therefore, the ACE2 levels need to be maintained besides inhibiting the entry of SARS-CoV-2. Thus, the usage of human recombinant soluble ACE2 (hrsACE2) which exhibited positive results in the phase I and phased II clinical trials to elevate the soluble form of ACE2that competes with the membranous ACE2 for binding with SARS-CoV-2 and inhibits the viral entry and replication can be considered as a therapeutic option to treat COVID-19. Besides inhibiting the viral entry, it also sustains the ACE2 levels required for the degradation of Ang II [153, 154] .

Currently, hrsACE2 has been approved as a treatment option of ARDS. African green monkey kidney derived cell line; namely, Vero E6 was cultured and infected with SARS-CoV-2.

Then the infected culture was added with hrsACE2 to estimate the therapeutic potential of hrsACE2. infection [153, 155] . Therefore, the usage of hrsACE2 can be a potential therapeutic option to inhibit the viral infection besides preserving the ACE2 levels and blood pressure in control. Since ACE2 is also the binding receptor for SARS-CoV-2 and enhances the viral entry, replication decreases the level of the ACE2, leading to reduced anti-atrophy and anti-fibrosis anti-inflammation, anti-oxidant, and vasodilation further leads to decreased tissue protection. On the other hand, there is a pro-atrophy, pro-fibrosis, pro-inflammation, vasoconstriction,pro-oxidant, and acute lung injury via angiotensin II type 1 receptor which leads to tissue injury. 

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The authors thank the VIT, Vellore, Tamilnadu, India, for supporting this work. The author KaviyarasiRenu is grateful to ICMR for providing financial assistance in the form of a Senior Research Fellowship (SRF).

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