key: cord-0865058-wh6cvqnp authors: Jayachandran, Swaminathan K.; Anusuyadevi, Muthuswamy; Essa, Mohamed Mustafa; Qoronfleh, M. Walid title: DECODING INFORMATION ON COVID – 19: ONTOLOGICAL APPROACH TOWARDS DESIGN POSSIBLE THERAPEUTICS date: 2020-11-27 journal: Inform Med Unlocked DOI: 10.1016/j.imu.2020.100486 sha: 0daa692ca7036e6892af245f1f910275eb9ddb35 doc_id: 865058 cord_uid: wh6cvqnp To date, no effective preventive or curative medical interventions exist against COVID-19, caused by Severe Acute Respiratory Syndrome corona virus 2 (SARS CoV-2). The available interventions are only supportive and palliative in nature. Popular among the emerging explanations for the mortality from COVID-19 is “cytokine storm”, attributed to the body’s aggressive immune response to this novel pathogen. In less than a year the disease has spread to almost all countries, though the mortality rates have varied significantly from country to country based on factors such as the demographical mix of the population, prevalence of comorbidities, as well as prior exposure to viruses from the corona family. This review examines the current literature on mortality rates across the globe, explores the possible reasons, thereby decoding variations. COVID-19 researchers have noted unique characteristics in the structural and host-pathogen interaction and identified several possible target proteins and sites that could exhibit control over the entry of SARS CoV-2 into the host, which this paper reviews in detail. Identification of new targets, both in the virus and the host, may accelerate the search for effective vaccines and curative drugs against COVID-19. Further, the ontological approach of this review is likely to provide insights for researchers to anticipate and be ready for future mutant viruses that may emerge in future. COVID-19, a highly contagious respiratory illness caused by Severe Acute Respiratory Syndrome Corona virus 2 (SARS CoV-2), is believed to have spread from animals to humans at the local meat and sea food market at Wuhan, the capital city of Hubei province, China (1) . At first the disease was assumed to be incapable of spreading between humans. Though initial outbreak in December 2019was reported only in Wuhan, soon cases were found in other parts of China among people not directly associated with Wuhan meat and seafood market, thus confirming that intra-human transmission was taking place. On January 30, 2020, World Health Organization (WHO) declared COVID-19a as global emergency (2) , and on March 11, 2020, upgraded it to a pandemic (3) . By mid August 2020, 20.6 million confirmed cases and 749,000 deaths were reported globally (4). As of mid-November 2020 these numbers have raised to53.2 million confirmed cases and 1.3 million deaths, across 220 countries. The rapidly accumulating research data related to COVID-19from different parts of the world has created a huge glut of data some of which are not readily relatable. An ontological approach expected to facilitate overall understanding of the biological process, furthering the likelihood of targeted drug development. Ontology can be defined as a set of concepts and categories in a subject area or domain that shows their properties and the relations between them. Generating molecular and genetic ontology involves analyzing proteins and genes in association with similar other molecules that may have control over various signaling pathways and developing common concepts. When the same ontological concepts describe two different species such as host and pathogen, it may provide fresh ways to understand the mutual interaction between their genes and proteins. Biological terminologies led by individual proteins and DNA's were programmed as huge data in computers with a facility to retrieve based on the user's command. The ontologies are terminologies or biological verbs collected from various research publications in the relevant area of research, and hence the retrieved information has high reliability for the ontological research application. Accordingly this review takes an ontological approach, and summarizes the results of coordinated work of interdisciplinary experts who did not neglect any angle of the drug development. This allows maximum possible predictions for development of targeted drugs with no or minimal adverse effects. The ontology provides common terminology that furthers J o u r n a l P r e -p r o o f communications between experts in different specialties engaged in the same quest, such as pharmacology, vaccine designing, personalized medicine preparation, and new target identification. As individual departments tend to prefer specialists in their own discipline, institutions may need to appoint a team leader with interdisciplinary expertise and ontological skills. Being able to identify specific gene or set of genes, which are activated or suppressed during the disease condition helps in targeted development of the new drug. The traditional manual approach makes it tedious to identify a single gene or gene set in a large group of genes, whereas gene ontology can more quickly identify the most likely genes and their products which make the drug development process more reliable, faster and cheaper. Hence gene ontology and different branches of biomedical ontology accelerates development of new drugs, new drug targets, as well as vaccine development. Various gene ontology consortia provide a platform that facilitates development of an integrated and controlled vocabulary of genes and gene products. Some of them---such as Gene Ontology (GO), Infectious Disease Ontology (IDO), and Vaccine Ontology (VO)-provide open source ontological databases to facilitate global cooperation. This paper discusses the utility of such databases in detail. The corona virus family contains four sub classifications: alpha, beta, gamma, and delta, longknown to infect non-human mammals and reptiles. The first infection on humans from a mutant zoonotic corona virus was the 2003 outbreak of Severe Acute Respiratory Syndrome (SARS). Since then, at least two more instances of previously non-pathogenic corona viruses infecting humans were reported, namely, Middle East Respiratory Syndrome (MERS) virus and SARS CoV-2 that causes COVID-19. Epidemiologists warn of the risk of more pandemics from mutated corona viruses in the future. In this context, the globally coordinated efforts of scientists to deeply understand and restrain this family of viruses from harming humans should be given top priority. SARS CoV-2 has undergone minimal genomic modification/mutation from the SARS CoV-1, which was responsible for killing 774 people in the 20003 outbreak (5). So far, three strains of corona viruses are believed to infect humans and potentially cause severe symptoms: MERS-CoV, SARS CoV-1, and SARS CoV-2. MERS virus is another species coming under the same genus that spread in Middle Eastern countries after its outbreak in 2012 and killed an estimated858 people by 2019 (6) . Although these viruses come under the same family with J o u r n a l P r e -p r o o f similarities in the molecular aspects, mode of spread, and similar clinical conditions among humans, the exhibited behavior of each is different from each other. This may be due to factors like rate of reproduction, zoonotic behavior, and type of clinical manifestation in the host. The reproduction rate of MERS is represented as R0 =1, while for SARS CoV it is between 1.7 to 1.9 and for SARS CoV-2 it is 2.5 making the latter reproduce faster than the other two (7 As of today, there is no specific treatment for COVID-19, and clinical management of the COVID-19 patients is through non-targeted therapies meant for management of the symptoms and preventing secondary bacterial infections, palliatives. As the infection spreads, there are also expectations of achieving herd immunity. The proposed therapies can be broadly classified into three categories :( 1) vaccines and new drugs, (2) drug repurposing of existing anti-viral drugs, and (3) non-anti-viral drugs and accessory therapeutic management strategies. Esteban et al in 2020 has extensively discussed vaccine development against COVID-19 (10), and the current review focuses on different aspects of designing vaccine using systems biology approach. Consequently it might be surmised that the development of a protein subunit vaccine against RBM may provide immunity against COVID-19 (11). In addition, common antigenic regions of current human corona viruses (SARS CoV-1, SARS CoV-2, and MERS) may remain unaltered in the sequence for a long period. Therefore, designing a protein subunit vaccine, targeting genetically conserved antigenic regions common to various species of corona virus is likely to yield preventive benefits that remain effective for several years. for bladder cancer. They reported many novel findings that include the genes associated with AE in the immune system, skin, and respiratory system while using against TB, whereas, they found genes associated with urinary complications in treating bladder cancer (15) . show significant activity as a protease inhibitor in vitro whereas Ritonavir is co-introduced to increase the half-life of Lopinavir (16) . Despite several studies, Lopinavir/Ritonavir combination has failed to show beneficial effects against the COVID-19 virus, and is no longer recommended (17, 18) . Another antiviral drug, Remdesvir, is now preferred for its comparatively beneficial effect to COVID-19 patients (19, 20) . Remdesvir is a nucleotide analog, which is believed to prevent viral reproduction (21) . Even though this drug is claimed to be the best in the market, till now there is no published evidence against any drugs with clinical evaluation proof. Another antiviral candidate under investigation is Favilavir(Favipiravir), selectively designed to inhibit the RNA-dependent RNA polymerase (RdRp) in RNA viruses (22) . Both of these drugs work on the same principle, but the problem is that these drugs are also capable of introducing a mutation in the viral genome that could make the virus even more dangerous. Even though these drugs are produced to inhibit viral reproduction, their beneficial effects are highly limited, and the adverse effects seem to be high that makes the drug fail in consecutive clinical trials (23) . After the COVID-19 outbreak, several research teams worked to modify existing antiviral drugs to deal with the new threat. Riva L et al 2020 has extensively analyzed more than 12,000FDA approved small drug-like molecules, out of which they found 100 molecules to inhibit the viral replication, which included 21 known antiviral drugs. Besides, they identified selected compounds namely MDL-28170, ONO 5334, and Apilimod in possessing antiviral activity in iPSC-derived pneumocyte-like cells and primary human lung model (24) . While the above work was performed extensively in the combination of in silico and in vitro models, others employed purely in silico works to identify potent inhibitors of viral replication (25) . Several non-anti-viral drugs are used currently in the treatment of COVID-19 symptoms. Among them, Chloroquine (CQ) and Hydroxy Chloroquine (HCQ) are the most prominent. Originally used as anti-malarial drugs, these were also used to treat chemoprophylaxis, rheumatoid arthritis, and some blood disorders, and more recently, to treat HIV. SARS CoV2 uses endosomes in the host cell for its survival and Golgi apparatus for its reproduction. Both intracellular organelles are active only in the acidic environment. CQ and HCQ, being weak bases, makes the vesicles less acidic, hence makes the viral survival tougher (26) . Also, these drugs potentially inhibit the IL-6 mediated inflammatory pathway, thereby help prevent the cytokine storm inside the host system. The problems associated with CQ and HCQ are their strong adverse effects such as J o u r n a l P r e -p r o o f nausea, vision impairment, digestive disorders, and most importantly prolongation of QT interval, which could lead to cardiac arrest (27, 28) .Despite the risks, CQ/HCQ is often used currently as a drug of choice to treat COVID-19. CQ/HCQ was officially approved by the FDA as an emergency alternative at the end of February 2020, which was revoked later, but the drug is still permitted in some other countries such as Brazil. Tocilizumab is another anti-inflammatory drug, used for the treatment of rheumatoid arthritis. It is a monoclonal antibody that specifically inhibits the IL-6 signaling thereby reducing the severity of the COVID-19 (29) . The non-antiviral drugs discussed above are used as antiinflammatory drugs to minimize secondary complications such as cytokine storm, rather than acting against the viruses. The mechanism of antiviral drugs discussed here was specified by the manufacturers, however, the inability of these drugs to stop viral replication indicates a need for more detailed studies related to host-pathogen interaction. Such in-depth understanding is vital to identify more vulnerability in the pathogen and develop drugs that target those. Apart from pharmacological management, convalescent plasma therapy (CPT) is also used to approach, a few systems biology platforms are currently available to analyze high volume data. Their outputs facilitate better understanding of various aspects of the host-pathogen interaction. A few key features of these system-based approaches are discussed below. Gene Ontology (GO) is a widely used online database and consortium used to attribute genes and ATPase subunit beta-1 (ATP1B1), and moderate reactivitywithAnoctamin-6 (ANO6) gene ( Figure. 1) . Interestingly, both these protein products of these genes are highly involved in lung disorders.. ATP1B1 gene codes for the beta chain of Na + /K + and H + /K + ATPases and also codes the subfamily of Na + /K + -ATPases. Na + /K + -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane (40) . Another study reported that digoxin, a cardiacglycoside, is effective in preventing the entry of the Chikungunya virus by blocking Na + /K + and H + /K + -ATPases pump after screening several clinically significant compounds through high-throughput screening (41) . (2019) reported that ATP1B1 is essential for normal lung function and the down regulation could lead to lung fibrosis (42) . These two studies revealed a strong link between ATP1B1 and viral entry into the host cell which has led us to suggest that this protein might be valuable in developing a drug against COVID-19. Another human host protein, ANO6, has been found (via GO) to be moderately reactive with COVID-19 infection is appears to be rarely fatal to younger individuals with healthy immune systems. Societies where COVID-19 mortality rates are high tend to have older residents with comorbidities (47) . Persons with pre-existing conditions such as diabetes, asthma, high blood pressure and obesity have higher risk of mortality from COVID-19. As on date, statistics that establish the extent and nature of comorbidity risk associated with COVID-19 are not available. Nevertheless, the relationship is evident when comparing the COVID-19 deaths of country or region with its usual leading causes of deaths. Figure 1 spondylitis, and other inflammatory spondylopathies. They reported that 40% enriched the sharing of GO terms for interleukin-10 receptor binding, regulation of immune response, and response to insulin for the above-mentioned diseases (50) . Hence, they strongly recommend that comorbidity, common pathways, and gene links should be incorporated into treatment plans. Since comorbidity is associated with higher death rates, the same phenomenon can be used to and obesity, thereby showing that in addition to genes and pathways, many drugs also shared common properties to treat these diseases (51) . Hence, we strongly believe that performing the comorbidity analysis for the COVID-19-induced clinical conditions may lead the researchers to identify some existing drug action-potential against the current pandemic. The data required for the analysis of comorbidity can be retrieved from OMIM, HPO, GAD and from DO databases. J o u r n a l P r e -p r o o f Age is an important parameter for the assessing COVID-19 death risk. As there are no authenticated reports available to date on age-based details of COVID-19 deaths, all agencies strongly suggest that the age is robustly associated with COVID-19 deaths correlating the few existing reports (Figure 2 ). The aging process is known to reduce lung function, by progressive loss of elasticity of the lung tissue, thus reducing the efficiency of breathing. Above a mean age of 65 years, morbidities such as diabetes, hypertension, and/or CVD are likely to set in, accelerating any age-related reduction in respiratory efficiency, make them highly susceptible for severe COVID-19 infection and high risk of death. Table 3 J o u r n a l P r e -p r o o f The population and age-related details of the below table were collected from the World Bank and the COVID-19 data were compared manually. A notable exception is Japan, which, despite 48% of the population being above 50 years, has very low CFR. The reasons might be speculated variously, perhaps a mix of healthier lifestyle practices, genetic factors, and higher levels of social discipline making the Japanese more likely obey instructions for social distancing, mask wearing and maintaining public hygiene. J o u r n a l P r e -p r o o f Figure 3 . Age-associated case fatality rate (CFR) in South Korea, Spain, China, and Italy. An increase in the age is directly proportional to the CFR and it is the only available data to date. Source https://ourworldindata.org/ Similar to VO and comorbidity databases, there are age-associated databases which provide information related to aging and related variables. JeneAge is one of such databases, exclusively dedicated for the ontological research of age-associated complications (52). This database provides information regarding the collection and integration of aging phenotype data including lifespan information, dietary restrictions, and chemical compounds (53) . However, this database is still relatively underused by COVID19 researchers. Hühne R et al (2018) used this database to study the gene network related to the lifespan (54) .The same strategy can be adopted to study likely age association of genes that are susceptible to SARS CoV-2 and other corona viruses. The following schematic representation explains the importance of the integrated ontological approach to find out effective vaccine and therapies to tame SARS CoV-2 virus, and eventually the entire corona virus family. 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