key: cord-1009168-elmi1flx
authors: Azu, O.O.; Olojede, S.O.; Lawal, S.K.; Oseni, S.O.; Rennie, C.O.; Offo, U.; Naidu, E.C.
title: Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) Infection: Microbiologic perspectives and Anatomic considerations for Sanctuary Sites
date: 2021-08-20
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.08.015
sha: 0ba948d029e578fd02f4365a1df7cffe7a8c113a
doc_id: 1009168
cord_uid: elmi1flx

INTRODUCTION: A significant chunk of global life - the economy, sports, aviation, academic, and entertainment activities- has significantly been affected by the ravaging outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) with devastating consequences on morbidity and mortality in many countries of the world. METHODS: This review utilized search engines such as google scholar, PubMed, ResearchGate, and web of science to retrieve articles and information using keywords like “Coronavirus”, “SARS-CoV-2”, “COVID-19”, “Origin of coronavirus and SARS-CoV-2”, “microbiology of coronavirus”, “microbiology of SARS-CoV-2”, COVID-19”, “Coronavirus reservoir sites”, “Anatomic sanctuary sites and SARS-CoV-2”, biological barriers and coronavirus”, biological barrier and SARS-CoV-2”. RESULTS: While this pandemic has caught the global scientific community at its lowest level of preparedness, it has inadvertently created a unified and wholesome approach towards developing potential vaccine (s) candidates by escalating clinical trial protocols in many countries of Europe, China and the United States. Interestingly, viral pathobiology continues to be an evolving aspect that potentially shows that the management of the current outbreak may largely depend on the discovery of a vaccine as the administration of known antiviral drugs are proving to offer some respite. Unfortunately, discontinuation and longtime administration of these drugs have been implicated in endocrine, reproductive and neurological disorders owing to the development of pathological lesions at anatomical sanctuary sites such as the brain and testis, as well as the presence of complex biological barriers that permit the entry of viruses but selective to the entrance of chemical substances and drugs. CONCLUSION: This review focuses on the microbiologic perspectives and importance of anatomical sanctuary sites in the possible viral rebound or reinfection into the system and their implications in viral re-entry and development of reproductive and neurological disorders in COVID-19 patients.

Coronavirus surfaced toward the end of 2019, as it was presented as a cluster of pneumonia infections in a city called Wuhan in an Asian country, China. It started spreading throughout the cities of China, and subsequently, increasing numbers of cases are recorded throughout the nations of the world [4, 5] . Toward the end of January 2020, the World Health Organization (WHO) described the COVID-19 outbreak as a public health issue of international concern and to demystify the magnitude of the outbreak. It was characterized as pandemic [6] .

Presently, over one hundred and seventy-seven million confirmed cases of SARS-CoV-2 globally in people had been tested so far, while the total number of SARS-CoV-2 cases continue to rise owing to the second and third waves. The death rate tolls over three million and eightytwo thousand and more incidence as the disease progresses. The epicentres of the current SARS-CoV-2 outbreak are primarily in developed countries, such as China, the United States of America, and European countries [7] . Also, there have been reports in the media of people who had recovered and tested positive for SAR-CoV-2 due to reinfection. This phenomenon of reinfection continues to be a mystery to health officials and researchers. It focuses on viral 'sanctuary sites' as seen in other infectious viral diseases like the HIV/AIDS pandemic. Whilst the understanding of the pathobiology of SARS-CoV-2 continues to evolve daily, and we examine the possibility (however remote) of viral sequestration in specific organs in the body (like the testis, thymus, brain) that provide some form of sanctuary to viral particles based on particle size and specific morphological configurations inherent in these micro-anatomical structures. This review, therefore, focuses on the known facts about the novel SARS-CoV-2 outbreak and the special consideration that should be given to the anatomical sanctuary sites in the body as possible contributors to viral reinfection in recovered COVID-19 patients.

J o u r n a l P r e -p r o o f Seven known coronaviruses can infect humans: HcoV-229E, HCoV-0C43, SARs-CoV, HCoV-NL63, HKU1, MERS-CoV, and SARS-CoV-2. These coronaviruses have four genera (Alpha, Beta, Gamma, and Delta). Four (4) of out the seven (7) , including HCoV-0C43, SARs-CoV, HKU1, and MERS-CoV and SARS-CoV-2, are beta while HcoV-229E and HCoV-NL63 are alpha [3, 8, 9] . The coronavirus genome has approximately 27-32 kb positive-sense singlestranded RNA and its encoding for three broad protein classes. The virion is about 90-120nm in diameter, surrounded by a lipid bilayer that enveloped the helical nucleocapsid structure and protected the genome [10] . The intact virion encodes several structural proteins such as 180/90-kDa spike (S) protein, a ∼50to 60-kDa nucleocapsid (N) protein, an 8-kDa envelope (E) protein, and the ∼23-kDa membrane (M) protein and also the group-specific proteins or accessory protein (Figure 1 ). These proteins are unique and specific to a strain of Coronavirus.

The primary functions of these proteins are still unknown but are believed to influence the pathogenesis, interaction of the virus, and host cells and support viral replication [11] . The first successful Isolation of SARS-CoV-2 by inoculating human airway epithelial cells was done with a bronchoalveolar-lavage fluid sample from a patient presented with pneumonia [12] . The whole-genome sequencing of SARS-CoV-2 was reported in 2019 after a sample was taken from a patient with pneumonia in South Korea. The Isolation was done by cell culture, and the isolated SARS-CoV-2 was named BetaCov/Korea/KCDC03/2020 [12] . Kim et al. (2020) further reported the morphology of SARS-CoV-2 from electron micrographic analysis, and the virus has a particle size of about 70-90 nm with a wide range of intracellular organelles within the vesicles. Kim et al. (2020) concluded the current diagnosis of SARS-CoV-2 is based on RT-PCR for the detection of the gene. Besides, causative agent isolation will enhance serological test development and rapid diagnostic tests.

J o u r n a l P r e -p r o o f

The route of transmission of pathogens remains an essential step in assessing, curtailing, and managing infectious diseases. Presently, the transmission route of SARS-CoV-2 has not been fully established, although some routes of transmission have been recently documented [13] . The novel outbreak, SARS-CoV-2, spreads through the respiratory tract as the dominant means, which is similar to the transmission route in SARS-CoV and MERS-CoV, however, with more severe infectivity. It has been confirmed that people contract this infectious outbreak through droplet transmission; other routes of transmission asides respiratory system are emerging.

Recently, transmission through aerosol has been suspected, but more evidence is needed to establish this finding [14] . More so, evidence of contracting SARS-CoV-2 on inanimate objects has been reported [14, 15] . The presence of this infectious disease was discovered on the cell phones, items, and door handle of infected persons for a few hours to several days, which aggravates the possibility of infections in individuals that touches their eyes, nose, or mouth after an encounter with these materials [16] . This finding corroborates with the previous study that reported different time maintenance of infection of SARS-CoV and MERS-CoV on inanimate surfaces [17] .

Some studies have confirmed the presence of SARS-CoV-2 RNA in the faecal samples of infected patients [18, 19] , which is an indication of active replication of the virus in patients' gastrointestinal tract and possible suggestion of faecal-oral transmission route of this infectious disease. Consequently, Munster et al. (2020) suggested that testing of SARS-CoV-2 should be extended to faecal samples [20] . Transmission through the ocular surface has been reported, but more studies are required to substantiate this finding [21] . It is worth noting that, no evidence of vertical transmission of SARS-CoV-2. However, the latest report suggested that vertical J o u r n a l P r e -p r o o f transmission should not be ignored owing to confirmation of two newborns tested positive for SARS-CoV-2 in Wuhan [22, 23] . Furthermore, there was no evidence of SARS-CoV-2 in the breast milk of infected patients, which possibly rule out the risk of transmission from breastfeeding [24, 25] . The ultimate path of transmission of SARS-CoV-2 remains the respiratory tract through a droplet means, though other routes and means that have been stated above are also essential and should not be ignored.

The previous outbreaks of SARS, MERS, four common coronaviruses (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1) and newly outbreak of SARS-CoV-2 shows the necessity to understand the mechanism(s) used by these viruses to attack the host immune system, involuntary orienting response, discover effective antiviral agents and development of a human vaccine [26] . The membrane ectopeptidases is the general protein family to which all the known cellular receptors are grouped into. The viral entry does not require the catalytic activity of these peptidases, but the activation of human Coronavirus (HCoVs) spike proteins requires coexpression of other host peptidases [27, 28] . Previous studies documented that cleavage and activation of SARS-CoV, MERS-CoV, and HCoV-229E spike proteins employed human transmembrane serine proteases for viral entry [29, 30] .

The receptor of HCoV-229E is human aminopeptidase N (hAPN), and it represents only CoV that infects non-ciliated cells because of its high expression in non-ciliated cells of the human bronchus [31] . The SARS-CoV and HCoV-NL63 employed Angiotensin-Converting Enzyme 2 (ACE2) for binding with cells [32, 33] . High expression of ACE2 in alveolar type I, alveolar type II, endothelial, and ciliated bronchial cells have been previously reported [34] . The receptor of MERS-CoV is dipeptidyl-peptidase 4 (DPP4), a different receptor with high expression in the J o u r n a l P r e -p r o o f epithelial tissues in the human body as well as the endothelial cells [35, 36] . Presently, only the receptor determinants for HCoV-HKU1, O-Acetylated Sialic Acid, and HCoV-OC43, the Nacetyl-9-o-acetylneuraminic acid are known, but their surface receptors remain unknown [37, 38] . The spike glycoprotein of SARS-CoV-2 has been described as the combination of known bat SARS-CoV and unknown Beta-CoV [39] . More importantly, it was evident from the latest fluorescent study that SARS-CoV-2 utilized the ACE2 cell receptors and employed the exact SARS-CoV mechanism of viral entry to the host cell [40] . been attributed to the severity of the disease and the high rate of death. In contrast, restriction in SARS-CoV replication has been linked to pneumonia that it usually presents [41] .

Coronaviruses (CoV) are a group of disease-causing viruses that has been a subject of intense research since the 1960s. This virus infects humans and other vertebrates with clinical manifestations such as severe lower respiratory infections (pneumonia) and common cold in humans; consequently, respiratory tract and gastrointestinal systems are affected [42] . The to a live animal market, where the source has been traced to either bat (Origin) and civet cat or pangolin as intermediate hosts ( Figure 2 ). Moreover, it has been established that this novel SARS-CoV-2 is zoonotic, which is an indication that it can spread from humans to animals in some conditions, but to this present moment, no evidence that pets can spread this novel virus to humans [43, 44] .

The magnitude, different reactions, and manifestations of disease in males and females are essential tools for understanding the impacts of an outbreak on the general populace, which would also help develop sex-based precision modalities for the prevention and treatment of the disease [45] . The sex-based disaggregating data revealed an equal number of SARS-CoV-2 cases in males and females; however, the latest reports show different patterns in susceptibility and mortality rates.

The data so far on the mortality rates have confirmed that male populations have a higher death rate than females. In a recent cohort study from Italy and China, it was established that males constitute a more significant percentage of the reported death tolls compared to females [46, 47] .

However, the clinical and scientific basis for disparity in mortality rates between each gender remains unknown. Still, a study has linked it to sex-based immunological differences [48] and a higher percentage of smoking in men relative to women [49] . In another study conducted on the plasma of 331 confirmed cases of CoV, females were shown to produce more antibodies against SARS-CoV-2 in their plasma than males [50] . Besides, the antiviral activities of estrogenic J o u r n a l P r e -p r o o f compounds have been previously described [51] , and since estrogen is more concentrated in females, this may probably be another piece of evidence. Moreover, literature has documented that the gene controls the immune system is on the X-chromosome [52] , and double Xchromosomes are found in the female, which gives an edge at combating the virus and exposes female to autoimmunity than male. Other studies have linked a higher level of haemoglobin in the blood of men compared to women as a possible reason why men are more likely to be susceptible to SARS-CoV-2 [53, 54] . All these reports are emerging pieces of evidence, and further investigations are needed to corroborate their findings ( Figure 2 ).

More so, data emanating from epicentres in different countries such as Italy and China have revealed that older people aged ≥ 65 years are at higher risk of severe SARS-CoV-2 [55] .

Another data emanated from China shows a substantial upsurge in the death rate in older people and low fatality cases in people under the age of 20 years [56] . Though preliminary data from China indicates that older people are more vulnerable, the latest data from the U.S. Center for Disease Control and Prevention (CDC) has shown that young people between the ages of 20 to 40 years old are also hit with SARS-CoV-2 outbreak. This finding is contrary to speculations at the onset of the SARS-CoV-2 pandemic. Furthermore, in another study on 56 patients, higher fatality cases were found in older patients than the young and middle-aged patients [57] . Thus, environmental or lifestyle factors may be contributing to the different age-related outcomes between both countries ( Figure 2 ).

Based on the preliminary reports, SARS-CoV-2 was more severe in patients with underlying medical conditions such as diabetes mellitus, hypertension, coronary artery diseases, chronic renal failure, cerebrovascular diseases, chronic obstructive pulmonary diseases, chronic lung diseases, and smoking habit [45, 55] . Recently published research that considered 355 patients revealed that just 3 out of 355 patients who died due to SARS-CoV-2 in Italy had no comorbidities [47] . This evidence suggests that patients with comorbidities constitute a more significant percentage of the dying population. According to the CDC, three significant comorbidities have been described as the most common underlying disease conditions that predispose to severe SARS-CoV-2. They include diabetes mellitus, chronic lung disease, and cardiovascular disease ( Figure 2 ). Among the three, diabetes mellitus is the most common underlying clinical condition in SARS-CoV-2 patients [45, 58] , followed by chronic lung disease, while the least is cardiovascular disease. Also, recent data from cases in the United States of America indicates that patients with respiratory diseases are at a higher risk of developing severe SARS-CoV-2 than those without manifestation of respiratory infections [45] .

The gestational period in humans is marked by physiological adaptive changes and a compromised immune system that predisposes pregnant individuals to become vulnerable to pathogenic diseases such as SARS-CoV-2 ( Figure 2 ). The information on the susceptibility of pregnant women, obstetrics, and neonatal outcomes is essential as the SARS-CoV-2 outbreak continues to spread among the general populace. Now, information on the assessment and treatment of SARS-CoV-2 infected pregnant women is scanty. This report makes it difficult to ascertain the potential risk of vertical transmission to the foetus via the placenta circulation.

Similar to SARS-CoV-2 infected non-pregnant women, good obstetrics and neonatal outcomes J o u r n a l P r e -p r o o f were reported by Luo and Yin in seven SARS-CoV-2 infected pregnant women [59, 60] .

However, these studies are not enough to substantiate the safety of antiviral therapies in pregnant women infected with SARS-CoV-2, the obstetrics outcomes, and neonatal outcomes. SARS during pregnancy has been previously linked to adverse neonatal outcomes such as neonatal death, preterm birth, intrauterine death, and intrauterine growth restriction [61] . In another study by Zhu et al. (2020) that examined the neonatal outcomes of 10 pregnant women infected with SARS-CoV-2, 6 cases of premature delivery were observed. More so, possible adverse neonatal outcomes such as premature labour, respiratory distress, abnormal liver function, fetal distress, and thrombocytopenia have been described [62] . Therefore, more studies are needed to establish safe treatment modalities, obstetrics, and neonatal outcomes of pregnant women infected with SARS-CoV-2.

As one of the advancements in contemporary medicine, solid organ transplantation has been successfully employed to replace failed organs caused by infection or diseases. This procedure has served as the most effective treatment of irreversible or terminal organ failure. More so, organ transplantation has been used to improve the quality of life in patients with final stage disease [63] .

The liver, kidney, pancreas, intestine, lung, and heart are the major organs that are customarily employed in organ transplantation [64, 65] . Unfortunately, despite the improvement in the quality of life of patients with end-stage organ failure, organ transplants have many complications, ranges from neurological, renal, gastrointestinal, hepatic, and cardiovascular, with disastrous morbidity and mortality [66] . These complications, therefore, make patient with organ transplants susceptible to multiple infections or diseases such as COVID-19. The emerging J o u r n a l P r e -p r o o f report revealed that early organ post-transplant infection of COVID-19 might lead to devasted morbidity and mortality rates and an increase in hospital admissions, which may pose a significant threat to the healthcare system [67] . Imperatively, patients that receive solid organ transplant are known to have impaired T-cell regulated immune response [68] ; therefore, they are susceptible to respiratory viral infections like influenza [69] . In addition, the Centers for Disease Control and Prevention have classified solid organ transplant recipients as people at high risk of severe morbidity from severe acute respiratory syndrome coronavirus (SARS-CoV-2) [70] . A recent systematic review and meta-analysis conducted between January and October 2020 reveal a surging number of hospital admission of solid organ transplant's patients infected with COVID-19 [71] .

A recent study has demonstrated the link between the ABO blood group antigen expression and their roles in many infections by serving as receptors or co-receptors for pathogenic microorganisms such as viruses and parasites [72] . This report is an indication that there is a precise interplay between disease transmission and ABO blood groups [73] . In a study of the SARS-CoV outbreak in a Hong Kong hospital, individuals with blood group O were shown to have very low odds of infection compared with individuals with blood groups A, B, and A.B.

This finding indicates the resistance of blood group O to SARS-CoV infection [74] . The possible explanation for this has been described concerning the similarity between the coronavirus envelope and that of HIV, which targets host cells through a viral adhesion glycoprotein (gp).

SAR-CoV has been previously described as a virus with 210 to 230 kDa glycoprotein that possesses 23 N-glycosylation sites and a wide range of structures for glycan analysis with 2 to 4 antennae that can support ABH epitopes.

Moreover, since the respiratory and gastrointestinal epithelium is the target of the SARS-CoV, there is a possibility that expression of ABH antigens on the S protein and host envelope glycosphingolipids are most common in human isolates. Also, human anti-A and monoclonal anti-A can block S protein-expressing A-antigen, such as the case of the envelope protein [74, 75] . The latter study emanated from China and has provided us with information on how certain blood groups may be susceptible to novel SARS-CoV-2 than the other. Another study compared the ABO blood group in 2,173 SARS-CoV-2 infected patients with non-infected people from the same geographical area. A higher risk of SARS infection was found in blood group A of the infected individual compared with non-infected blood group A. In the same study, the lower risk of SARS-CoV-2 infection was observed in blood group O of the infected patients compared to the blood group O of non-infected individuals [76] . This study has given us more direction about the association between the blood groups and coronavirus susceptibility (Figure 2 ). Further studies are needed to validate this evidence.

While anatomical' sanctuary sites' could become viral reservoirs wherein the virus may become sequestered with the tendency of causing viral rebounds or reinfection after remission, there are still many aspects of this new pathogen-causing SARS-CoV-2 that is yet to be fully unravelled.

As research intensifies, it will become more evident to researchers why the binding processes of the viral skeleton trigger the immune responses that ultimately shut down the functionality of many organs and systems in the body as well as why some specific categories of individuals and sex respond aggressively to the viral infection than others. The anatomical sanctuary sites are common extra lymphatic organs, such as the lung, testis, kidney, brain, genital tract, lymph nodes, and blood [77] [78] [79] , that could encourage viral escape. They are the sources of drug-J o u r n a l P r e -p r o o f resistant, which makes virus eradication and cure difficult such that viral rebound inevitably occurs once antiviral is stopped [80] . The biological barriers that exist between the blood and different organs of the body serve as a defense mechanism against the spreading of toxins and infection to different organs [81] .

Testis, as an anatomical sanctuary organ, presents a biological barrier known as the Blood-Testis Barrier (BTB), a unique barrier with complex structural configuration (Figure 3 ). This barrier comprises adherent junction, tight junction, desmosome, tubulobulbar complex, ectoplasmic specialization, gap junction, and hemidesmosome [82] . The BTB forms demarcation that protects the functional parts of the seminiferous tubule from infectious disease, toxins, foreign bodies, and hormonal imbalance that may disrupt the reproductive function [83] . A prior study has shown the importance of the drug transporters and receptors at the junction of these barriers as determinants of the level of chemicals and drugs that can enter the testis both in disease and healthy situations [84] . The brain is another anatomical sanctuary organ that also has a Blood-Brain Barrier (BBB). This biological barrier functions to protect the brain tissue from harmful substances, pathogens, and toxic substances [85] . BBB permits the passage of viruses but restricts the penetration of certain drugs [86] . Specific receptors and carrier proteins have been described as determining factors for the entry of essential nutrients and substances through BBB [87] .

Another biological barrier is the Blood-Thymus Barrier (BThB), a physiological and selective barrier that separates T-lymphocytes from the blood and the cortical capillaries inside the cortex of the thymus [88] . This barrier is formed by many layers of cells that primarily serve to impede the movement of macromolecules from the vascular environment to the trabeculae of the cortex. [81] . Thymic epithelial cells do not permit the transport of macromolecules and foreign antigens, but it allows the exchange of tiny molecules through their high density of intercellular junctions and the membrane transporters [89] . Various conditions and factors such as sex hormones, adrenocorticotropic hormone, stress, and glucocorticoids can compromise the integrity of the BThB. More so, they can pave the way for the entry of foreign antigens into the cortex of the thymus, consequently, lead to impaired immunity [88] . The thymus has been described as a target for various infections that may affect the actions of the peripheral T-lymphocytes [90] . The expression of the ACE2 has been discovered in the thymus, which could make the thymus susceptible to the tropism of the novel SARS-CoV-2.

The Blood-Air Barrier (BAB) is a functional barrier formed by the two alveolar epithelial cells of the peripheral lung [91] . The alveolar epithelial type I (ATI) cells account for 90-95% of the alveolar surface with large size, while alveolar type II (ATII) cells are cuboidal in shape, smaller in size, and represent 5% of the alveolar surface [92] . The alveolar type I cell create a large surface area for the exchange of air and involved in the transport of protein and ion. In contrast, alveolar type II participated in the production of surfactant and are progenitor cells for ATI cell regeneration [93, 94] . The BAB is of clinical significance in the drug delivery system [95] . There was a report that aerosol drug administration to the respiratory system allows the delivery of both macro and micro molecules. Moreover, it aids the rapid absorption of drugs and avoids the firstpass effect [91] . High expression of ACE2 has been widely documented in the human airways J o u r n a l P r e -p r o o f and lung parenchyma [34, 96, 97] . This expression implicates BAB in SARS-CoV-2 infectivity as long as the required quantity of ACE2 receptors is available.

The importance of anatomical sanctuary sites in disease pathogenesis cannot be overemphasized.

Anatomical sanctuary organs can bring about the reactivation of pathogens, including viruses, during immunocompromised conditions, such as pregnancy, chemotherapy, organ transplants, and stress, and consequently complicate virus elimination [98] . Emerging reports from the latest published fluorescent studies show that SARS-CoV-2 uses Angiotensin-Converting Enzyme II (ACE2) receptors as the mechanism of viral entry and infect the host cells [40, 99] . ACE2 is expressed at the RNA and protein levels in many tissues and organs in the human body (Table   1 ). Other studies have reported high expression of ACE2 in the alveolar type I and type II epithelial cells. Also, in the Leydig cells and spermatogenic cells of the seminiferous tubules of the testis. This evidence may lead to lung and testicular tissue damage after SARS-CoV-2 infection [100, 101] . Since ACE2 has been confirmed to be the significant structural and functional receptor that mediates the entry of SARS-CoV-2 into the human cells, there is a high possibility that most ACE2 expressing tissues in the body may be potential reservoir sites for SARS-CoV-2 infection and reactivation. Interestingly, a newly published study on thirty SARS-CoV-2 infected patients has reported SARS-CoV-2 in the semen of four infected patients and the urine of seven patients (102) . This study has shown that urogenital tracts harbours SARS-CoV-2 and may serve as a viral reservoir site.

The latest finding documented the expression of ACE2 receptor in the brain tissue to neuronal pathogenicity of SARS-CoV-2 [103] . The presence of SARS-CoV2 was detected in the cerebrospinal fluid of SARS-CoV-2 patients [104] . The expression of ACE2 receptors has been previously reported in the neurons and neuroglia. This evidence shows the susceptibility of the J o u r n a l P r e -p r o o f brain tissue to SARS-CoV-2 ( Figure 4) . Similarly, neuronal death has been attributed to the SARS-CoV presence in the brain tissues, which may have escaped into the brain through olfactory epithelial cells of the nasal cavity [105] . The pieces of evidence mentioned above implicate the anatomical sanctuary sites/organs in the pathogenesis and possible reinfection of SARS-CoV-2 in recovered patients. Also, the multi-tissue expression of ACE2 receptors, as seen in the testis, small intestine, kidney, among others, may provide a hiding site for SARS-CoV-2 in the body and aid the prolonged pathogenicity and viral re-entry into the systemic circulation (Table 1 ). This evidence may be responsible for the multiple waves of cytokine storms observed in SARS-CoV-2 patients, as well as multi-organ failures, including reproductive, digestive, urogenital, and neurological disorders.

In addition to the ACE 2 receptors, the latest findings have shown that SARS-CoV-2 can use Transmembrane serine protein 2 (TMPRSS 2) and Cathepsin (CatB/L) for cell entry [106] .

Furthermore, recent reports have underscored the expressions of ACE 2 and TMPRSS 2 [107] and the cathepsin L in different regions of the brain [108, 109] .

A recent preliminary study has shown high expression of TMPRSS 2 was observed in the lung, a target tissue for SARS-CoV-2, the testis, prostate gland, kidney, colon, intestine, thyroid gland, and the breast. Therefore, the transmembrane protein expression could make these tissues susceptible to the entry and tropism of the novel SARS-CoV-2 [110] .

Cathepsin L is involved in many diseases' conditions such as viral infection, metabolic disorders, cancer, inflammatory conditions, musculoskeletal disorders, and renal diseases. Expressions of the cathepsin L receptors in the human lung epithelial cells have been reported [111] . This lysosomal enzyme's expression is up-regulated in the chronic inflammatory process and J o u r n a l P r e -p r o o f participates in lowering the extracellular matrix, an essential activity for the entry of SARS-CoV-2 into the host cells [112] .

This review employed the available literate to explore the microbiologic perspectives. Also, it suggests that for the management of SARS-CoV-2 infection involving antiviral drugs, careful consideration of the anatomical sanctuary sites as hiding places for SARS-CoV-2 and the presence of pathologic lesions must be taken seriously. This is as a result of emerging reports on COVID-19 points to the possibility of reinfection or viral reactivation. Currently, coronaviruses have neither been reported to encode an integrase like enzyme nor have such mechanisms previously described for HIV. However, HIV infection has been proven to encode an integrase enzyme that facilitates the integration of the viral genome into the host cellular genome. This mechanism is responsible for evading the host's immune system and rebound when antiretroviral drugs are withdrawn or when favourable conditions arrive. Therefore, future research should look toward encoding enzyme and mechanism that supports SARS-CoV-2 replication and rebound at the withdrawal of antiviral drugs currently used to manage the chronic SARS-CoV-2 infection.

Careful diagnostic and prognostic modalities should be put in place to check for viral localization in anatomical satellite sites before discharging recovered or asymptomatic patients.

In addition, long-term effects of viral tropism and the pathophysiology of SARS-CoV-2 in anatomical satellite organs/sites need to be studied to understand this disease better and eradicate or manage it. This understanding would be beneficial to prevent viral reactivation and viral complications, such as reproductive dysfunction, neurological disorders, endocrine disorders, kidney problems, and liver disorders. trandolapril(https://www.medicinenet.com/ace_inhibitors/article.htm#why_are_ace_inhibitors_pr escribed_uses); Transmembrane protease, serine 2 (TMPRSS2) inhibitors drugs like, Nafamostat mesylate, Camostat mesylate, Aprotinin, Rimantadine (https://www.rndsystems.com/target/tmprss2inhibitors) and Cathepsin inhibitors [113] . These drugs could be used synergistically with other drugs to prevent viral invasion. Hence, it could serve as a prospect for SARS-CoV-2 control.

All authors have read and accepted responsibility for the content of the manuscript

Authors hereby declare that no funding for this review work.

Authors hereby declare no conflict of interest J o u r n a l P r e -p r o o f 

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Prevalence and patterns of tobacco smoking among Chinese adult men and women: findings of the 2010 national smoking survey

A comparison study of SARS-CoV-2 IgG antibody between male and female COVID-19 patients: a possible reason underlying different outcomes between gender. medRxiv

Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors

The X chromosome in immune functions: when a chromosome makes the difference

Flawed methods in "COVID-19: Attacks the 1-Beta Chain of Hemoglobin and Captures the Porphyrin to Inhibit Human Heme Metabolism

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis

Epidemiology and Transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts

Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients

Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection?

Management of pregnant women infected with COVID-19

Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study. The Lancet Infectious Diseases

A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome

Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia

Why is organ transplantation clinically important?

Organ transplantation in the modern era

Challenges in organ transplantation

Complications of Solid Organ Transplantation: Cardiovascular, Neurologic, Renal, and Gastrointestinal

Significant impact of COVID-19 on organ donation and transplantation in a lowprevalence country

T-cell responses following Natural Influenza Infection or Vaccination in Solid

A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients

Coronavirus Disease 2019 -People of Any Age with Underlying Medical Conditions

COVID-19 in solid organ transplant recipients: A systematic review and meta-analysis of current literature

Blood groups in infection and host susceptibility

ABO blood group and susceptibility to the severe acute respiratory syndrome

Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies

Identification of N-linked carbohydrates from severe acute respiratory syndrome (SARS) spike glycoprotein. Virology

Relationship between the ABO Blood Group and the COVID-19

Highly active antiretroviral therapy (HAART) and testicular morphology: current status and a case for a stereological approach

Renal epithelium is a previously unrecognized site of HIV-1 infection

Lung epithelial cells are a major site of murine gammaherpesvirus persistence. The Journal of experimental medicine

HIV reservoirs, latency, and reactivation: prospects for eradication

Regulation of spermiogenesis, spermiation and blood-testis barrier dynamics: novel insights from studies on Eps8 and Arp3

Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development

The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters

The dynamic blood-brain barrier. The FEBS journal

Drug transfer across the blood-brain barrier and improvement of brain delivery

Application of nanomedicine for crossing the blood-brain barrier: theranostic opportunities in multiple sclerosis

The discovery of the blood-thymus barrier

Negative selection-clearing out the bad apples from the T-cell repertoire

The thymus is a common target organ in infectious diseases

Isolation, cultivation, and Application of human alveolar epithelial cells, in Human Cell Culture Protocols

Cell number, and cell characteristics of the normal human lung. American Review of Respiratory Disease

Alveolar epithelial type II cell: defender of the alveolus revisited

Alveolar type I cells: molecular phenotype and development. Annual review of physiology

Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier

ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on the differentiation of human airway epithelia

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

the transmission of lymphocytic choriomeningitis virus by organ transplantation

Evolution of the Novel Coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

A human homolog of angiotensin-converting enzyme cloning and functional expression as a captopril-insensitive carboxypeptidase

ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection

The presence of SARS-CoV-2 virus in semen samples of patients with COVID-19 pneumonia

evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

Letter to the Editor Regarding the Viewpoint "Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanism

Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2

Mu¨ ller, Christian Drosten, Stefan Po¨ hlmann. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

The expression of SARS-CoV-2 receptor ACE2 and CD147, and protease TMPRSS2 in human and mouse brain cells and mouse brain tissues

Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia

Cathepsin L participates in the production of neuropeptide Y in secretory vesicles, demonstrated by protease gene knockout and expression

Expression and co-expression analyses of TMPRSS2, a key element in COVID-19

Expression of Cathepsins B and L in Human Lung Epithelial Cells is Regulated by Cytokines

Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics

Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients

Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways

The clinical pathology of severe acute respiratory syndrome (SARS): a report from China

Lung pathology of the fatal severe acute respiratory syndrome. The Lancet

Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated Coronavirus in the lung of a fatal case of severe acute respiratory syndrome in Taiwan

Positive rate of RT-PCR detection of SARS-CoV-2 infection in 4880 cases from one hospital in

ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation

Severe acute respiratory syndrome-associated Coronavirus is detected in intestinal tissues of fatal cases

Detection of severe acute respiratory syndrome (SARS)-associated coronavirus RNA in autopsy tissues with in situ hybridization. Di June 1 yi da xue xue bao= Academic journal of the first medical college of PLA

Angiotensin-I-converting enzyme and its relatives

Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes

The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes. medRxiv

Angiotensin I-converting enzyme type 2 (ACE2) gene therapy improves glycemic control in diabetic mice

Characterization of ACE and ACE2 expression within different organs of the NOD mouse. International journal of molecular sciences

An update on the islet renin-angiotensin system

ACE2 gene expression is up-regulated in the human failing heart

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia

A clinicopathological study of three cases of severe acute respiratory syndrome (SARS)

Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin-converting enzyme

Multiple organ infection and the pathogenesis of SARS. The Journal of experimental medicine

Possible central nervous system infection by SARS coronavirus. Emerging infectious diseases

Table 1: Tissue distribution of Angiotensin-Converting Enzyme II receptors (ACE2) in tissues/organs and currently reported the detection of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 in anatomic satellite organs

The authors hereby appreciate the University of KwaZulu-Natal Language Centre for the editing service