Understanding on the possible routes for SARS CoV-2 invasion via ACE2 in the host linked with multiple organs damage

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accountable for causing the coronavirus diseases 2019 (COVID-19), is already declared as a pandemic disease globally. Like previously reported SARS-CoV strain, the novel SARS-CoV-2 also initiates the viral pathogenesis via docking viral spike-protein with the membranal angiotensin-converting enzyme 2 (ACE2) — a receptor on variety of cells in the human body. Therefore, COVID-19 is broadly characterized as a disease that targets multiple organs, particularly causing acute complications via organ-specific pathogenesis accompanied by destruction of ACE2+ cells, including alveolus, cardiac microvasculature, endothelium, and glomerulus. Under such circumstances, the high expression of ACE2 in predisposing individuals associated with anomalous production of the renin-angiotensin system (RAS) may promote enhanced viral load in COVID-19, which comparatively triggers excessive apoptosis. Furthermore, multi-organ injuries were found linked to altered ACE2 expression and inequality between the ACE2/angiotensin-(1–7)/mitochondrial Ang system (MAS) and renin-angiotensin-system (RAS) in COVID-19 patients. However, the exact pathogenesis of multi-organ damage in COVID-19 is still obscure, but several perspectives have been postulated, involving altered ACE2 expression linked with direct/indirect damages by the virus-induced immune responses, such as cytokinin storm. Thus, insights into the invasion of a virus with respect to ACE2 expression site can be helpful to simulate or understand the possible complications in the targeted organ during viral infection. Hence, this review summarizes the multiple organs invasion by SARS CoV-2 linked with ACE2 expression and their consequences, which can be helpful in the management of the COVID-19 pathogenesis under life-threatening conditions.

(B.1.427) and Kappa variant (B.1.617.1), by November 2021. However, on 26 November 2021, WHO announced the advent of a new SARS-CoV-2 mutant called Omicron (B.1.1.529), which is directly classified under VOC due to its high transmission frequency and increased risk of infection (WHOa; WHOb). Notably, both experimental and computational studies have deciphered the highly contagious characteristics of identified seven SARS-COV-2 mutants, suggested the function of favorable mutations in the RBD region to exhibit higher binding affinity with the human ACE2 receptor (Harvey et al., 2021;Kim et al., 2021;Socher et al., 2021;Tian et al., 2021). For example, using steered molecular dynamics simulations and microscale thermophoresis analyses on the S-protein in SARS-CoV-2, Alpha, Gamma, Beta, and Delta variants were sequentially categorized for demonstrating stronger interactions with the hACE2 receptor followed by Kappa and Epsilon variants against the wild type (WT) strain of SARS- CoV-2 (Kim et al., 2021). Likewise, experimental analysis on S-protein of Omicron mutant showed its comparable binding affinity with the human ACE2 receptor against WT strain, but weaker than the Delta variant (Wu et al., 2022). Besides, computational analysis of S-protein marks the Omicron with an advanced risk of immune evasion (Wu et al., 2022). The alterations in the RBD region of S-protein on the various variants of SARS-CoV-2 that contributed to an increase or decrease in binding affinity with the hACE2 receptor are summarized in Table 1.

Molecular fate of ACE2 under SARS-CoV-2 invasion
host IFN responses could, thus, stimulate the capability of the virus to preserve cellular targets expression in neighboring epithelial cells (Ziegler et al., 2020). Remarkably, screening of nonstructural proteins plus structural proteins of SARS-CoV-2 supports the S-protein to facilitate the IFN-α effector, which further encourages the IFN-stimulated genes (ISGs) signaling and radically enhanced the production of long ACE2 protein in the bronchial epithelial cell line BEAS-2B , as depicted in Figure 2. Mechanistically, upregulation of long ACE2 protein was demonstrated with higher phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 as a result of reinforcing their signaling with upstream Janus kinase, i.e., JAK1, by S-protein of SARS-CoV-2 to aid viral access in the bronchial epithelium . Likewise, IFN-γ was noted to promote cellular differentiation into enterocytes expressing ACE2, supporting the high viral infection and replication (Heuberger et al., 2021). In another study, exposure to IFN-γ and IFN-λ caused a robust increment in the production of ISGs and ACE2 protein in nasal AE cells of infants (Salka et al., 2021). Meanwhile, internalization of virus-ACE2 complex and ACE2 degradation, resulting in the reduction of membranal ACE2 protein (Heyman et al., 2021). This results in augmented production of angiotensin II (Ang II) and causes reduced production of respective counter regulating angiotensin (1-7) molecules (Miesbach, 2020). Besides, ADAM-17 (shedase) activation by Ang II further contributes to the reduction in the membranal ACE2 receptor (Patel et al., 2014). Altogether, the depletion of ACE2 and Ang-(1-7) in the tissue causes inequality between the RAS and ACE2/angiotensin-(1-invasion in the host cell (Ziegler et al., 2020). These assumptions were coherent with the observation that the expression of ACE2 in endothelial cells was augmented under acute COVID-19 as a corollary of the host's responses to viral infection (Klouda et al., 2021). Therefore, the feasible dual functions of IFNs during SARS-CoV-2 pathogenesis seek stringent supervision of infected individuals, those are under treatment using IFN as a therapeutic approach (Su and Jiang, 2020).

Relationship of ACE2 with multi-organ injury in SARS-CoV-2 infection
Given that SARS-CoV and SARS-CoV-2 belonged to the same group and employed the common membranal ACE2 protein as a functional receptor on the host cells, convincing results from the sequence of investigation on SARS-CoV strain proposed that SARS-CoV-2 pathogenesis should be multiplex, comprising virus-induced inflammatory responses, extreme recruitment of inflammatory cells, auto-antibodies formation, expression of cytokines and chemokines, and altered interferon responses Osuchowski et al., 2021;Parasher, 2021). For instance, considerable concentrations of chemokines plasma-like interleukin (IL-1, IL-6, IL-12, and IL-8), monocyte chemoattractant protein-1 (MCP-1), interferon-gamma-inducible protein 10 (IP-10), and pro-inflammatory cytokines (PICs) were examined in the plasma of infected populations by SARS-CoV (Wong et al., 2004). Besides, autopsy of SARS-affected individuals also supported the mentioned observations, where MCP-1 and PICs were distinguished remarkably in infected ACE2 + cells by SARS-CoV by comparison to non-infected ACE2 + cells, represented the substantial contribution of local immune-intermediated injury in response to the viral infection (He et al., 2006). Surprisingly, analogous promoted expression of PICs was also detected in the plasma of acute COVID-19 patients . Moreover, various findings acknowledged that the elevated expression of the membranal ACE2 induced by the onset of viral infection accelerates viral homing, but it was impaired by shedding and degradation during viral infection, which directed to Ang-(1-7) molecules depletion after infection; thereof, such events encouraged the overwhelming clinical symptoms of COVID-19 (Cao et al., 2020;Yan et al., 2021). Meanwhile, with the assumption that SARS-CoV-2 primarily targets the respiratory system, expression analysis of ACE2 protein based on stringent J o u r n a l P r e -p r o o f immunohistochemical tests suggested no or least ACE2 expression in a subtype of cells from the upper respiratory system (Hikmet et al., 2020). In contrast, under co-localization with mucin 1 (MUC1) + cells, ACE2 expression was demonstrated only within the type II pneumocytes of the lung (Lee et al., 2020); these results support the findings of ACE2 expression in type II pneumocytes predicted by single-cell RNA-sequencing (scRNA-seq) data analysis (Sungnak et al., 2020;Ziegler et al., 2020) and single antibody chromogenic staining method (Bertram et al., 2012;Hamming et al., 2004). Moreover, a concurrent Human Cell Atlas (HCA) Lung Biological Network analysis also detected the TMPRSS2 and ACE2 genes expression in other tissues enriched in nasal ciliated and goblet cells (Sungnak et al., 2020). For instance, the conceited expression of ACE2 was found in the eye, myocardial cells, placental trophoblasts, vasculature, male reproductive cells, ductal cells, bladder urothelial cells, enterocytes in the ileum region, and proximal tubule cells in the kidney (Hamming et al., 2004;Hikmet et al., 2020;Zhang et al., 2020c). Hence, given the substantial expression of ACE2 in several organs and as a receptor of SARS-CoV-2, the cell-free and phagocytosis-associated virus particles were suggested to travel through blood circulation to other susceptible organs of the host with the prominent display of ACE2 receptor   (Fig. 2). Consistent with it, multi-organ damages, such as acute lung and kidney injuries, heart injury, liver disease, and pneumothorax, were examined mostly in the severe SARS-CoV-2 infected individuals Shi et al., 2020a;Yan et al., 2021). Furthermore, the intestinal and other epithelia were stated for invasion by SARS-CoV-2 via active replication and de-novo production of infective virus (Bwire et al., 2021;Wang et al., 2020b;Xiao et al., 2020). Therefore, initially pathogenesis of SARS-CoV-2 infection as COVID-19 was marked for severe respiratory disease only; however, later established that infected patients by SARS-CoV-2 can promptly continue to multi-organ dysfunction syndromes (MODS) (Lopes-Notably, SARS-CoV-2 infection occurs due to the activation and priming of its S-protein by the TMPRSS2 protein followed by the attachment to the membranal ACE2 protein on the host cells (Hoffmann et al., 2020). Successively, the excessive representation of ACE2 receptors on the different types of epithelial cells in the respiratory tract was classified for high susceptibility to infection by SARS-CoV-2 . However, despite being included in the initial targets, the manifestations related to the respiratory system, such as pneumonia and ARDS, were not always the primary symptoms and other comorbidities have been identified in severe COVID-19 disease, including prevalent hypertension (HTN), illness, obesity, diabetes mellitus (DM), and respiratory illness (Bian and Li, 2020;Kang et al., 2020;Shi et al., 2020b;Yang et al., 2020a). Moreover, cells expressing ACE2 protein in the intestinal epithelium, heart, kidney, vascular endothelium, lung (mostly type II alveolar cells), and smooth muscles; thus, such cells have been marked for invasion of SARS-CoV-2 that resulted in COVID-19 associated multi-organ failure or MODS (Lopes-Pacheco et al., 2021). Besides, the strong inflammatory responses caused by the viral infection in the lungs and other organs were suggested to cause multi-organ failure. For instance, upon entrance into the cells, SARS-CoV-2 stimulates T-lymphocytes, which elicits a strong immunological response as well as an inflammatory response. This results in the initiation of the inflammatory cascade and the generation of cytokines, including interferon-γ (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukins (IL-1 and IL-6), and tumor necrosis factor-α (TNF-α), at an elevated rate than usual production under the phenomenon termed cytokine storm (CS), which ultimately leads to tissue damage Zhang et al., 2020d). Nevertheless, the exact cause of extrapulmonary symptoms is still obscure; however, several variables, including direct/indirect secondary damage by an inflammatory response generated against the invasion of the virus, have been suggested Zhang et al., 2020d).
reported that 25-29% of the deceased and acutely sick patients of COVID-19 were detected with AKI Lee et al., 2020). On the first day of admission, 34% of the patients had shown renal abnormalities, whereas 63% of all the patients developed proteinuria during the hospitalization (Adukia et al., 2020). Another research on COVID-19 demonstrated that 26.7% of patients showed symptoms of hematuria on admission while 44% of patients developed proteinuria and hematuria during hospitalization . This was in accordance with the autopsy data, which advocated the endothelium damage in the kidney of infected patients and probably contributed to proteinuria (Varga et al., 2020). Also, the level of blood urea nitrogen (BUN) was noticed at around 27 and 66% in enduring and deceased COVID-19 patients, respectively . Furthermore, recent findings elucidated that SARS-CoV-2 infected persons with a history of prolonged kidney diseases and hypertension are at greater risk for AKI (Guan et al., 2020a;Henry and Lippi, 2020). For instance, a recent study identified 32 COVID-19 patients with subclinical AKI displaying the high concentration of kidney tubular injuries (KTI) biomarkers, such as retinol-binding protein, N-acetyl-D-glycosaminidase, 1microglobulin, and 2-microglobulin (Canatan et al., 2020;. Furthermore, assessments of post-mortem kidney samples from COVID-19 patient with AKI at stage 2 or 3 also revealed severe tubular damage as by far the most frequent finding in kidneys, typified by mainly moderate focal critical tubular necrosis (Golmai et al., 2020;Legrand et al., 2021;Santoriello et al., 2020;Schurink et al., 2020). These observations were coherent with the autopsy study of 6 patients with COVID-19, where microdissection of kidneys showed the presence of SARS-CoV-2, specifically enriched in the glomerulus (Puelles et al., 2020). Additionally, viral particles of SARS-CoV-2 were identified in the urine samples of COVID-19 patients (Sun et al., 2020b) -a discovery that either suggests the delivery of the virus from infested and broken renal tubular cells expressing ACE2 receptor (Li et al., 2003) or the separation of viral splits, as 2020; . In support, RNA and protein of SARS-CoV-2 were identified during the assessment of infected kidneys using in situ hybridization with confocal microscopy (Puelles et al., 2020). Likewise, SARS-CoV-2 was identified in the renal endothelial cells, signifying viremia as a probable trigger of damage in endothelial tissue of the kidney and an apparent sponsor to AKI (Varga et al., 2020). Moreover, macrophage activation syndrome, endotheliitis, rhabdomyolysis, and advancement of microemboli and microthrombi in the context of hypercoagulability were also deciphered to promote AKI under SARS-CoV-2 infection (Varga et al., 2020;Zhang et al., 2020e). Thus, a substantial clinical characteristic of SARS-CoV-2-induced renal dysfunction implied that SARS-CoV-2 holds the potential to infect the kidney tissue; however, a direct role of the virus in the AKI development yet needs to be confirmed (Santoriello et al., 2020). Altogether, the mechanisms behind COVID-19 renal dysfunction remain uncertain and was suggested as a multifactorial mechanism with predisposing factors as an important contributor to AKI, including (i) direct association of virus trailed by the replication in the kidneys, ensuing in the imperfect renal function; (ii) local disturbance in renin-angiotensin-aldosterone system (RAAS) balance; (iii) dysregulation of SARS-CoV-2-interrelated immune retorts, specified by cytokine storm and lymphopenia, (iv) cardiovascular comorbidity and predisposing issues (e.g., nephrotoxins sepsis, and hypovolaemia) (Diao et al., 2021;Hirsch et al., 2020;Kunutsor and Laukkanen, 2020;Ronco et al., 2019;Ronco and Reis, 2020). Therefore, additional research is required to understand the pathophysiology behind renal dysfunction triggered by SARS-CoV-2, which will aid in the development of appropriate treatment options. human liver ductal organoids expressing TMPRSS2 and ACE2 receptors were demonstrated to recapitulate SARS-CoV-2 replication, indicating the susceptibility of epithelium in the bile duct for virus invasion and resulting in direct cholangiocyte injury and subsequent bile acid accumulation . Likewise, human pluripotent stem cell-derived liver organoids containing particularly hepatocytes with albumin were also demonstrated for ACE2 expression and infiltration of SARS-CoV-2 pseudoparticle . In support, post-mortem analysis of liver tissue from acute COVID-19 patients using electron microscopy reveals possible coronavirus-like nanobodies in the cytoplasm of hepatocytes along with swelling in mitochondria and apoptosis . Conversely, an in-depth proteomic evaluation of autopsy tissue from COVID-19 patients (19 individuals) showed little indication for the dynamic SARS-CoV-2 replication in the liver (Nie et al., 2021). Besides, hepatic protein signatures suggested the upregulation of profibrotic pathways, dysregulation of fatty acid oxidation and oxidative phosphorylation, and immune activation; such variations in the proteomic display can be linked with the manifestation of coagulative hepatocyte necrosis and hepatic steatosis (Nie et al., 2021). Moreover, the patients with persistent liver infections, especially with pre-existing cirrhosis, were marked for horrendous consequences in COVID-19 and connected to respective immunocompromised conditions . Therefore, the liver lesions have been marked as minor and transitory conditions, but remarkable damage may occur in the liver of severely SARS-CoV-2 infected individuals under poor prognosis (Chaibi et al., 2021). In addition, several reports have described hepatotoxicity in COVID-19 patients as drug-induced liver injury (DILI) (Sodeifian et al., 2021). For instance, DILI was noted to enhance the expression of liver enzymes by several medications, such as hydroxychloroquine and remdesivir, used in the treatment of SARS-CoV-2 infection (Sodeifian et al., 2021). Therefore, a conclusive mechanism for liver injury in COVID-19 is still obscure, and further in vivo research is required on SARS-CoV-2 induced damage in the liver. cardiovascular complications are considered as delayed complications in infected individuals, which may appear suddenly during hospitalization or even after improvement in their respiratory health (Fried et al., 2020;Lang et al., 2020). Therefore, the onset of acute cardiovascular injury caused by COVID-19 has been linked with an absolute poor prognosis (Giustino et al., 2020;Labbe et al., 2021). For instance, COVID-19 individuals diagnosed with cardiac injury were noted for a high ranking of mortality (51.2-59.6%) by comparison to the patients with no cardiac injury (4.5%-8.9%) during hospitalization Shi et al., 2020a). Nevertheless, clinical data suggested that the vulnerability and consequences of COVID-19 were effectively connected to cardiovascular diseases (CVD), such as arrhythmias, myocardial injury, venous thromboembolism, and acute coronary syndrome (ACS) (Nishiga et al., 2020). A recent analysis based on single-cell RNA sequencing reported that myocardial cells (more than 7.5%) showed a high presentation of ACE2 protein (Zou et al., 2020), which may accelerate the incursion of SARS-CoV-2 into cardiomyocytes and initiate immediate cardiotoxicity. In support, some cases of COVID-19 were detected for the occurrence of SARS-CoV-2 particles in the cardiac tissue by reverse transcription-polymerase chain reaction (RT-PCR) (Yao et al., 2020b), indicating that direct cardiotoxicity may induce by SARS-CoV-2 infection. Such assumptions were further supported by in vitro studies demonstrating the efficient infection and replication of SARS-CoV-2 in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) expressing ACE2 receptor (Bailey et al., 2021;Marchiano et al., 2021;Perez-Bermejo et al., 2021;Perez-Bermejo et al., 2020). Of note, infected hPSC-CMs were also characterized for cessation of beating (Sharma et al., 2020), compromised electrophysiological function (Marchiano et al., 2021), transcriptional and morphological signatures of damage (Perez-Bermejo et al., 2021), impaired contractile function (Bailey et al., 2021;Marchiano et al., 2021), and cell death (Bailey et al., 2021;Marchiano et al., 2021). Furthermore, autopsy and endomyocardial biopsy specimens' analysis of 4 cases with COVID-19 highlights the presence of SARS-CoV-2 protein in cardiomyocytes but not in cardiac fibroblasts, macrophages, or endothelial cells (Bailey et al., 2021). Likewise, among the autopsies of 39 cases of COVID-19, RNA of SARS-CoV-2 was identified in the myocardium of 24 patients while only negative-sense RNA, which indicates the active replication of SARS-CoV-2, was discovered in the myocardium of 5 patients suffering from J o u r n a l P r e -p r o o f the highest viral load (Lindner et al., 2020). In another autopsy report of 41 COVID-19 cases, 30 cases showed the manifestation of SARS-CoV-2 RNA in the heart while the myocardium contained the least number of cells infected by SARS-CoV-2 (Bearse et al., 2021). In contrast, no viral antigens were identified in the heart amongst autopsy specimens from five COVID-19 patients, but all the patients were diagnosed with acute myofibrillar anomalies (Bailey et al., 2021). Likewise, post-mortem analysis of all 8 patients with COVID-19 showed no mark of SARS-CoV-2 particles in the heart detected by immunohistochemistry, in situ hybridization, or qRT-PCR approach (Massoth et al., 2021). Thus, the involvement of direct invasion of SARS-CoV-2 in cardiomyocytes to in vivo pathogenesis remains unclear. Under another perspective for cardiac manifestations produce in COVID-19, SARS-CoV-2 has been described to initiate a systemic immune response, including activation of inflammatory pathways, and was suspected to promote the myocardial injury in SARS-CoV-2 infected population . For example, pro-inflammatory cytokines, like TNF-α, IL-1, and IL-6, were suggested to produce a negative inotropic effect on cardiac contractility in COVID-19 patients (Li et al., 2021b).
Meanwhile, TNF-α was deduced to produce a constant stimulation of inflammatory signalling to trigger extensive cardiomyocyte programmed cell death, resulting in pathological remodelling of the left ventricle; and eventually, leading to acute heart failure (Li et al., 2021b). Thus, under SARS-CoV-2 infection, virus-induced hyper inflammation with cytokine discharge can result in direct myocardial suppression and inflammation, plaque instability, hypercoagulable state, and vascular inflammation (Prabhu, 2004). Therefore, biomarkers related to inflammation along with cardiac troponins, fibrinogen, D-dimer, and natriuretic peptides have been suggested for concurrent examination (Canatan et al., 2020). Collectively, COVID-19 cardiovascular syndrome must be managed by a multidisciplinary approach involving cardiologists, intensive supervision, and infectious disease specialist.
with COVID-19 was suggested due to direct neuroinvasion by SARS-CoV-2 or indirectly by peripheral infection coupled with virus-induced immune responses (Iadecola et al., 2020). Thus, considerable interest has been centered on the neuroinvasion of SARS-CoV-2, which has returned contradictory conclusions (Cantuti-Castelvetri et al., 2020;Jacob et al., 2020;Matschke et al., 2020;Meinhardt et al., 2021;Pellegrini et al., 2020;Song et al., 2021). For instance, systematic analysis of the brain showed no molecular marks for the incursion of SARS-CoV-2, but distinctive cellular perturbations were observed, demonstrating that cell barrier of the choroid plexus sense and assist in the transmission of induced peripheral inflammation to the brain, and also aid the infiltration of peripheral T cell into the parenchyma .
Moreover, microglia and astrocyte subpopulations were noticed for association with COVID-19 that reveal pathological characteristics of the cell as previously studied in human neurodegenerative disease (Frigerio et al., 2019;Keren-Shaul et al., 2017). Meanwhile, the viral genome of SARS-CoV-2 was found in the cerebrospinal fluid (CSF) and in the brain of some COVID-19 cases, encouraging the supposed neuroinvasion by SARS-CoV-2 (Iadecola et al., 2020;Paniz-Mondolfi et al., 2020;Puelles et al., 2020). Besides, viral RNA and proteins or virus-like nanobodies were identified in the blood and brain endothelial cells, respectively (Andersson et al., 2020;Cantuti-Castelvetri et al., 2020;Paniz-Mondolfi et al., 2020;Song et al., 2021), implying neuroinvasion of SARS-CoV-2 via the hematogenous channel. Also, SARS-CoV-2 infection in the pericyte underlies the invasion of the virus into the restricted central nervous system (CNS) space as well as neurological symptomatology because of inflammation in perivascular spaces and compromised local blood-brain barrier (BBB) (Bocci et al., 2021). For instance, magnetic resonance imaging in COVID-19 patients demonstrated the formation of lesions formation that was consistent with a cerebral small-vessel disorder and BBB disruption Conte et al., 2020;Radmanesh et al., 2020). This interpretation was in accordance with the autopsy studies Matschke et al., 2020;Reichard et al., 2020). In the infected brains of humans and animal models, enhanced production of empty basement membrane tubes--also named string vessels, indicating the remains of lost capillaries, which proved that SARS-CoV-2 main protease (M pro ) holds the potential to digest the nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) essential modulator (NEMO)--an essential regulator J o u r n a l P r e -p r o o f of NF-κB; hence, highlights the viral infection in the endothelial cells of the brain (Wenzel et al., 2021). Collectively, the reported studies indicate virus-induced damages both in the peripheral and central nervous systems of COVID-19 patients. Also, more than 35% of COVID-19 individuals were noted for the development of neurological symptoms as the condition progresses. For instance, COVID-19 patients presented both peripheral neurological manifestations (PNM), including skeletal muscle damage, complete or partial loss of smell (anosmia) and taste (ageusia), and Guillain Barrè syndrome (GBS) and central neurological manifestations (CNM), which comprises headache, dizziness, acute transverse myelitis, encephalopathy, acute hemorrhagic necrotizing encephalopathy, and cerebrovascular accident (Ahmad and Rathore, 2020;Filatov et al., 2020). However, the cause of such complications is still unclear, whether they are directly related to the hypoxic metabolic changes, viral infection or, post-infection auto-immune reactions (Ahmad and Rathore, 2020;Filatov et al., 2020).

Central nervous system manifestations
The prevailing central nervous system (CNS) symptoms, including dizziness and headache in 16.8 and 13.1% cases, respectively while the rare symptoms such as ataxia, consciousness, seizure, cerebrovascular disease, nerve pain, and vision impairment in 0.5, 7.5, 0.5, 2.8, 2.7, and 1.4% cases, respectively were documented in the COVID-19 patients. Moreover, symptoms such as malaise, headache, and myalgia were commonly noted in the early stages of neurological syndromes while under severe COVID-19 cases, altered sensorium was also observed that results in confusion, delirium, and stupor followed by coma as the final stage, detailed reviewed elsewhere (Ahmad and Rathore, 2020). Therefore, patients enduring acute COVID-19 have been marked for a greater incidence of neurological signs and symptoms, which may be attributed to cerebral hypoxia triggered by respiratory failure (Ahmad and Rathore, 2020).

Peripheral nervous system manifestations
The remarkable symptoms of the peripheral nervous system (PNS) in COVID-19 patients included hyposmia, anosmia, hypogeusia, ageusia, GBS, and muscular soreness while a rare incidence for spinal cord involvement was also reported (Mao et al., 2020). Also, anosmia and/or J o u r n a l P r e -p r o o f ageusia were studied as the most prevalent PNS symptoms in SARS-CoV-2 infection. For instance, in a European study, the olfactory dysfunctions and/or gustatory dysfunctions were observed in 85.6 and 88.0%, respectively among mild to moderate enduring COVID-19 patients.
However, the prevalence of infection was higher in women, including 44% of cases displayed early olfactory recovery while the symptoms resist for up to 14 days before full recovery (Lechien et al., 2020). Of note, olfactory symptoms were noted for sudden appearance accompanied by less severe nasal symptoms, including nasal obstruction or immoderate nasal discharge (Lechien et al., 2020). Moreover, the occurrence of ageusia and anosmia was noted in most of the individuals without any other symptoms (Mao et al., 2020).

Hematological dysfunction
Recent In this context, COVID-19 patients enduring thrombocytopenia were observed with epistaxis, lower-extremity purpura, and neurological manifestations, such as headache, suggested due to According to recent research, infection instigated by SARS-CoV-2 might result in cutaneous involvement in enduring patients with severe COVID-19 (Behzad et al., 2020). For instance, a study on 88 patients showed that generalized urticaria, erythematous rash, and chickenpox-like blisters were the main skin manifestations under COVID-19 while observed skin lesions were mildly irritating and mainly observed in the trunk of the body (Recalcati, 2020).

Reproductive system dysfunction
Although high expression of ACE2 has been documented in the male reproductive system by comparison to the female's, thus, growing evidence have indicated that reproductive systems in Meanwhile, in males, a study using single-cell RNA sequencing claimed that the ACE2, which is expressed in Leydig cells, germ cells, and Sertoli cells in the testis, can be infected by SARS-CoV-2 (Shen et al., 2020), suggested the testicular tissue as a reservoir as well as tropism site for SARS-CoV-2 . In this context, male patients were studied with low sperm count along with reduced sperm motility as post-infection consequences of COVID-19, which continued for up to three months (Guan et al., 2020a). Also, male patients were reported with congestion, red blood cell exudation in testes, interstitial edema, and epididymitis as well as thinning of seminiferous tubules post-COVID-19 infection, suggested impaired spermatogenesis as a consequence of COVID-19 in male patients (Li et al., 2020). Therefore, recovered male patients were advised for the semen examination as well as testicular and reproductive functions. Further, external genital pain was also reported in rare cases of COVID-19 in male J o u r n a l P r e -p r o o f patients (Özveri et al., 2020). However, the process by which SARS-CoV-2 invaded the reproductive system in humans remains elusive.

Ophthalmic manifestations
Under COVID-19, high chances for the ocular manifestations have been suggested in the form of local or transitory vasculitis due to the ACE2 expression on endothelial cells and enhanced vascularity of conjunctiva (Gu and Korteweg, 2007;Ho et al., 2020). Thus, SARS-CoV-2 was detected to cause a wide range of ophthalmic symptoms, including conjunctivitis, anterior uveitis, retinitis, and optic neuritis (Ulhaq and Soraya, 2020; Wu et al., 2020;Zou et al., 2020). Of note, 2 to 32% of prevailing symptoms in ocular functions were related to COVID-19 severity

Endocrinal manifestations
The association between blood sugar level and respiratory illnesses is widely known (Baker et al., 2006). The COVID-19 is being connected with an increment in blood sugar levels among diabetics' people experiencing poor control . For example, research studies suggested that greater than 50% of all confirmed or probable COVID-19 patients had an increased levels of blood sugar (hyperglycemia) and approximately 33% of patients were suffering from diabetic ketoacidosis (Thaweerat, 2020). There are possibilities that SRAS-CoV-2 directly affects the pancreas; since, the pancreas exhibit enhanced expression of ACE2 receptors along with the inflammatory responses that may direct to pancreatic failure in severe COVID-19 patients (Thaweerat, 2020). Moreover, these consequences were also associated with the elevated concentrations of serum lipase and/or amylase (Banks et al., 2013). Consequently, it is J o u r n a l P r e -p r o o f critical to control and monitor the blood sugar level in infected diabetic patients for the management of COVID-19.

Microbial Co-Infections in COVID-19
Microbial coinfection has been noticed to play a critical role in SARS-CoV  . In some cases, patients with prior chronic bacterial infections developed the chronic obstructive pulmonary disease (COPD) after infection by SARS-COV-2 . Moreover, it has also been reported that co-infection with SARS-CoV-2 and HIV (human immunodeficiency virus) may impair the immune system, abnormal polyclonal activation, damage T-cells, and may further contribute to the prolongation of COVID-19 .

Clinical approaches for COVID-19 management
The unpredictable and heterogenous symptoms ranging from mild and moderate up to severe  Table 1. Consistent with it, a set of infected population displayed only mild to moderate symptoms such as headache, fever, cough, sore throat, fatigue, malaise, muscle pain, vomiting, nasal congestion, and diarrhea Guan et al., 2020b;Huang et al., 2020). Therefore, the mode of medical treatment in COVID-19 patients has been recommended based on the signs and symptoms of infection.  Table 4. Consistent with it, new antiviral oral pills named molnupiravir and paxlovid were claimed effective in COVID-19 management by reducing the number of deaths as well as hospitalizations in clinical trials (Harrison, 2021;Ledford, 2021). Also, the combination of drugs

Conclusion and Remarks
SARS-CoV-2 virus damages almost every organ within the body; and therefore, multiple symptoms are being associated with COVID-19 currently. To avoid the worst situation becoming and complicated, every case must be evaluated promptly and with high suspicion. SARS-CoV-2 and its emerging mutants have a high potential not only to infiltrate the lungs but also holds the potential to damage other organs due to the substantial expression and distribution of ACE2 receptors in various vital organs and tissues of the human body. Additionally, rapidly growing literature also suggested the S-protein of SARS-CoV-2 contained a furin cleavage site, indicating that S-protein is highly susceptible for the activation beyond TMPRSS2 by a broad range of host proteases (Bugge et al., 2009;Coutard et al., 2020;Walls et al., 2020). Besides, activation of IFN signalling induced by S-protein was also noted to support the elevated expression of ACE2 receptor, which may facilitate viral entry . Therefore, the cause of multiple organ damage in individuals affected with COVID-19 is suggested due to the involvement of   Moderate symptoms include fever along with pneumonia and occasionally silent pneumonia with silent hypoxia. Severe symptoms include acute respiratory distress syndrome (ARDS) in the second week of infection followed by respiratory failure and death.

Renal dysfunction infection
 Elevated markers of proteinuria, hematuria, blood urea nitrogen (BUN), and creatinine in the serum during hospitalization.  These symptoms worsened into acute kidney injury (AKI) and consequently resulted into death. Other frequent skin manifestations include chilblain-like lesions, especially localized on fingers and toes.  Least common symptoms include vesicular, purpura, livedoid eruption, and papulovesicular lesions.


In females, enduring with polycystic ovary syndrome (POCS) were found more susceptible to SARS-CoV-2 infection.  Damage in ovaries and imbalance in reproductive hormones were marked for altered reproductive system functions.  Vertical transmission of COVID-19 from a pregnant mother to the newborn child has also been reported.  In males, congestion, red blood cell exudation in testes, interstitial edema, and epididymitis as well as thinning of seminiferous tubules and impaired spermatogenesis was noted as post effects of COVID-19. Also. two symptoms (central retinal vein occlusion and rhino-orbito-cerebral mucormycosis) were observed along with the acute, subacute, and delayed symptoms.