key: cord-0696333-r2ynbnxx
authors: Mohapatra, Ranjan K.; Pintilie, Lucia; Kandi, Venkataramana; Sarangi, Ashish K.; Das, Debadutta; Sahu, Raghaba; Perekhoda, Lina
title: The recent challenges of highly contagious COVID‐19, causing respiratory infections: Symptoms, diagnosis, transmission, possible vaccines, animal models, and immunotherapy
date: 2020-07-26
journal: Chem Biol Drug Des
DOI: 10.1111/cbdd.13761
sha: c6e3f4e919a16456ae69f702a23de15550cb0903
doc_id: 696333
cord_uid: r2ynbnxx

COVID‐19 is highly contagious pathogenic viral infection initiated from Wuhan seafood wholesale market of China on December 2019 and spread rapidly around the whole world due to onward transmission. This recent outbreak of novel coronavirus (CoV) was believed to be originated from bats and causing respiratory infections such as common cold, dry cough, fever, headache, dyspnea, pneumonia, and finally Severe Acute Respiratory Syndrome (SARS) in humans. For this widespread zoonotic virus, human‐to‐human transmission has resulted in nearly 83 lakh cases in 213 countries and territories with 4,50,686 deaths as on 19 June 2020. This review presents a report on the origin, transmission, symptoms, diagnosis, possible vaccines, animal models, and immunotherapy for this novel virus and will provide ample references for the researchers toward the ongoing development of therapeutic agents and vaccines and also preventing the spread of this disease.

and hence, termed as coronavirus (Latin: corona means crown). The genome (nucleic material) size varies from 26 to 32 kbs in length (Shereen, Khan, Kazmi, Bashir, & Siddique, 2020) . There are four subfamilies, namely alpha-, beta-, gamma-, and deltacoronaviruses, exist till date. The alpha-and betacoronaviruses are originated from mammals (bats), whereas gamma-and deltacoronaviruses are originated from birds and pigs. There are seven human coronaviruses identified till date (Table 1 ; Chan et al., 2020; Franquet, 2011; Hansell et al., 2008; Lee, 2020; Malainou & Herold, 2019) . Among these seven subtypes, betacoronaviruses are causing severe diseases and fatalities, while alphacoronaviruses cause mildly symptomatic infections. As per the genomic analysis, SARS-CoV-2 is identical with bat CoV (96%) and pangolin CoV (86%-92%), so bats could be the possible primary reservoir (GISAID, 2020; Shereen et al., 2020; Zhou, Yang, et al., 2020) . The major four structural genes encode the spike protein (S), nucleocapsid protein (N), membrane glycoprotein (M), and small membrane protein (SM) with an additional hemagglutinin esterase (HE) if present (HE is only present in some betacoronaviruses). The genome RNA is complexed with N protein to form a helical capsid structure and found within the viral membrane. Trimers of S protein give the virion a crown-like shape. In some cases, HE protein also forms smaller spikes (Figure 1 ). SARS-CoV-2 is a new strain of CoV for humans making the pandemic coronavirus disease . It is a pathogenic viral infection initiated from Huanan Seafood wholesale market of Wuhan (Hubei province, central China) on 31 December 2019, where seafood and live animals were sold Li, Guan, et al., 2020) . This recent outbreak of novel CoV has expanded throughout China and spread rapidly around the whole world due to onward transmission (Lipsitch, Swerdlow, & Finelli, 2020) . The virus was confirmed by Chinese authorities on 7 January 2020 (Lu, Stratton, & Tang, 2020; WHO, 2020a) and the transmission appeared to be from animals into human (Chan et al., 2020; Hui et al., 2020; Nishiura et al., 2020) . The exact route of transmission is not clear yet. But the spike protein (S) may binds to ACE2 as an entry receptor for viral entry into the host cell and infects lung alveolar epithelial cells (Franquet, 2011; Kirchdoerfer et al., 2016; Xu, Chen, et al., 2020) . After penetration into the body, all RNA-related machinery will be hacked. These viruses are responsible for diarrhea in pigs and cows and respiratory diseases in chickens. The animal-specific viruses are not normally infecting humans. But, may cause life-threatening pneumonia due to novelty of the virus, if they pass to humans. This is really very dangerous for the immune-suppressed individuals having diabetes, cardiovascular diseases and leads to pulmonary failure.

The important consequence of COVID-19 is pneumonia means this virus infects mainly respiratory system . It may be transmitted through respiratory droplets and even via fecal-oral transmission (Chan et al., 2020; Wang, Cao, et al., 2020) . That means the human coronaviruses are transmitted from one infected person to another mainly by direct contact through saliva, coughing or sneezing (within a range of about 1-1.5 m). Presently, there are no specific drugs or vaccines available for the treatment of human CoV (Han, Lin, Jin, & You, 2020) . Therefore, it is very essential to understand the nature of this virus and its clinical characteristics. For this widespread zoonotic virus (Table 2) , human-to-human transmission has been confirmed in more than 83 lakh cases of nearly 213 countries and territories as on 19 June 2020 (WHO, 2020). The common clinical symptoms for current COVID-19 are fever, dry cough, dyspnea, muscle soreness, headache, anosmia, and fatigue (Wang, Tang, & Wei, 2020) . Initially, about 20% of cases were severe, and mortality rate was approximately 3% (Wang, Horby, Hayden, & Gao, 2020) . For which, WHO has declared a global health emergency on 30 January 2020 (Mahase, 2020) . It was too early to conclude the mortality rate. From the closed cases, the recent mortality rate is reached at ~9%, which may vary depending upon the current cases. Furthermore, the outbreak has destroyed the global economy and stock market. This is the seventh CoV which infect humans and other two are SARS and MERS. According to Jung et al., the current epidemic has a substantial potential for causing global pandemic (R 0 > 1) . This study will make a brief report on 2019-nCoV, which may be helpful for the researchers as well as society. (Booth et al., 2003; Dwosh, Hong, Austgarden, Herman, & Schabas, 2003; Lee et al., 2003; Tsang et al., 2003; Weiss & Leibowitz, 2011; WHO, 2003) . This acute and often severe CoV was spread via airborne droplets and through fomites (Donnelly et al., 2003) , which have infected nearly 8,000 peoples with 778 deaths (WHO, 2003) before the episode was shutdown. The coronavirus virion structure (Finlay & Hancock, 2004 ) is shown in Figure 1 . As per the phylogenetic analyses, it was placed in the early branch of betacoronaviruses category and the genus includes MHV (Snijder et al., 2003; Zhu & Chen, 2004) . The patients infected by SARS-CoV, showed fever, sore throat, nonproductive cough, and myalgia in the first phase of the illness. In the second phase, dyspnea, hypoxia, and diarrhea with continued fever became more prominent followed by severe lung damage. Deaths occurred from day 4 and severity of the disease increased with age, with mortality 50% for patients over 60 age (Booth et al., 2003; Lee et al., 2003; Tsui, Kwok, Yuen, & Lai, 2003) . Initially, it was suggested that Himalayan palm civets (Paguma larvata) and raccoon dogs (Nyctereutes procyonoides) as possible sources for human infections (Guan et al., 2003) . But civets in the wild did not have evidence of infection with SARS-CoV and the discovery of SARS-like bat coronaviruses with approximately 90% sequence identity with SARS-CoV in Chinese horseshoe bats (Rhinolophus sinicus) suggests that this or a related species of bat is likely origin of SARS-CoV (Lau et al., 2005; Li et al., 2005) . At early phases, the lungs of infected humans contained hyaline membranes, small vessel thrombi, edema, fibrin exudates, loss and sloughing of pneumocytes, and a mixed cellular infiltrate of lymphocytes. Whereas, at later phases, pneumonitis and consolidation with type II pneumocyte hyperplasia, squamous metaplasia and bronchiolitis obilterans was found (Beijing Group, 2003; Cameron et al., 2007; Wong et al., 2004 ).

The novel lethal MERS coronavirus infection was first identified from Jeddah, Saudi Arabia in June 2012 (Bauerfeind et al., 2016; Zaki, van Boheemen, Bestebroer, Osterhaus, & Fouchier, 2012) . The case was noticed in a man who was admitted to the hospital with pneumonia and acute kidney injury (McIntosh, Hirsch, & Thorner, 2017) . A similar virus with 99.5% identity was reported from Qatar in September 2012 who had traveled to Saudi Arabia before the disease progression exacerbated (Wise, 2012) . Since then, nearly 2,500 confirmed human infections have been reported in 27 countries with mortality rate more than 30% (WHO, 2020b). The virologic research revealed that this infection was originated by dromedary camels (Camelus dromedarius), which infects human respiratory tract (Al-Tawfiq, 2013; . All related cases have been noticed in Middle East, East Asia, North Africa, Europe, and United States (WHO, 2018) . This novel zoonotic virus is responsible for acute human respiratory syndrome and the dromedary camels of East Africa and Arabian Peninsula are only the confirmed animal host with DPP4 receptor (Conzade et al., 2018; Falzarano et al., 2017; Miguel et al., 2017; Perera et al., 2013; Ramadan & Shaib, 2019; Reusken, Haagmans, et al., 2013) . Humans are believed to acquire MERS-CoV though contact with camels, camel products, and consumptions (Azhar, Hui, Memish, & Zumla, 2019) . This virus is closely related with bats' coronaviruses, suggesting bats may be the possible natural reservoir (Ramadan & Shaib, 2019) , but not unconfirmed yet. Also, no vaccine is available for MERS-CoV till date. Epidemiological and viral sequence data suggested that camels are the main culprit for virus transmission to humans .

Camel meat is a common food and important source of nutrition for people in Middle East and African countries. (Sohrab & Azhar, 2019; Zumla, Chan, Azhar, Hui, & Yuen, 2016) , which will be very valuable to design the therapeutic compounds and vaccines to prevent MERS-CoV disease. The schematic representation for the genome organization of human betacoronaviruses is shown in Figure 2 . The antibody-based therapeutic modalities have received significant attention for the treatment of many diseases (Hu et al., 2019; Qiu et al., 2014; Zhu et al., 2006) . Based on that, Wang et al., 2019 have reported the generation of antibody-peptide bispecific fusion proteins for clinical use. The efficacy of a ChAdOx1 MERS vaccine in dromedary camels (seronegative and seropositive) was studied by Alharbi et al., 2019 . From the study, it was cleared that antibody responses in seropositive camels were enhanced by using a single dose of this vaccine.

The novel CoV (2019-nCoV) infection was initiated from Wuhan of China, in December 2019 (Lu, Stratton, et al., 2020) and has been spread to almost all countries. On 11 February 2020, WHO announced the name "COVID-19" for this epidemic disease caused by a new, viral, zoonotic pathogen 2019-nCoV. This virus was again renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (Gorbalenya et al., 2020) . Also, WHO declared COVID-19 as the sixth public health emergency of international concern (PHEIC). SARS-CoV-2 is closely related to bat-SL-CoV-ZXC21 and bat-SL-CoVZC45 and spread by human-to-human transmission via droplets or direct contacts (Carlos, Dela Cruz, Cao, Pasnick, & Jamil, 2020; Chang et al., 2020; Li, Guan, et al., 2020; Wang, Hu, et al., 2020) . Moreover, the hospital-related transmission was also suspected in 41% of patients . The infection may have mean incubation period of 6.4 days and a basic reproduction number of 2.24-3.58. In this period, the patient may not display any symptoms (asymptomatic). The most common symptom for COVID-19 is fever, pneumonia followed by cough. As per computed tomography images of chest, bilateral lung involvement with GGO is the most common finding (Lai, Shih, Ko, Tang, & Hsueh, 2020) .

Emerging infections were shown among pregnant women and their fetuses (Rasmussen & Hayes, 2005) with the increased risk of complications with H1N1 influenza (Siston et al., 2010) and Zika virus (Moore et al., 2017; Rasmussen, Jamieson, Honein, & Petersen, 2016) . Basing on that, Chen, Guo, et al., 2020 have reported the cesarean data for nine COVID-19 patients in their third trimester. The patients had F I G U R E 2 Genome organization for human betacoronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), (Adapted with Permission from Shereen et al., 2020, Journal of Advanced Research, © Elsevier BV.) fever (seven), fever with cough (four), myalgia (three), sore throat (two), and malaise (two). Fetal distress was also observed in two cases. Furthermore, five patients had lymphopenia and three patients had increased aminotransferase concentrations. Nine live births were recorded. No neonatal asphyxia was observed in newborn babies. Amniotic fluid, neonatal throat swab, cord blood, and breast milk samples were tested and found negative for the virus. The clinical characteristics of pregnant women were similar with non-pregnant patients. Since small number of cases analyzed, so more follow-up studies should be done to evaluate the safety and health of pregnant women having COVID-19 infection (Qiao, 2020) . Zhu, Xu, et al. (2020) ) have reported first time the clinical characteristics of a 52-year-old COVID-19 patient, who had received kidney transplantation 12 years ago. The overall clinical features were similar with non-transplanted COVID-19 patients. The patient was successfully recovered with low-dose methylprednisolone-based therapy. These data may be helpful for the future treatment of such type of patients.

The epidemic has spread from China to 212 countries and territories. According to WHO as on 19 June 2020, the number of confirmed cases of COVID-19 is 8,385,440 (WHO, 2020). The countries like USA, Brazil, Russia, India, UK, Italy, Spain, France, Germany, Turkey, Saudi Arabia, Peru, Chile, Pakistan, Mexico, Bangladesh, and Canada have reported more positive cases. The outbreak has killed 4,50,686 people to date. Moreover, Gilbert et al., 2020 have evaluated the preparedness and vulnerability of African countries against their risk toward COVID-19. As per their study, Algeria, Egypt, and South Africa have highest importation risk, whereas, Sudan, Angola, Nigeria, Ethiopia, Tanzania, Kenya, and Ghana have moderate risk. Hence, it is most important to provide necessary epidemiological data so that appropriate decisions are made regarding Paralympic Games, Tokyo 2020 Olympic and similar type of mass gatherings (Gallego, Nishiura, Sah, & Rodriguez-Morales, 2020 ).

To examine the possibilities of domestic animals as reservoir, serological studies were performed on sheep, goats, cattle, and chickens in Saudi Arabia, UAE, Jordan, and Europe. All samples tested seronegative for MERS-CoV (CDCP, 2016; Hemida et al., 2013; Meyer et al., 2015; Reusken, Ababneh, et al., 2013; Reusken, Haagmans, et al., 2013) . But, dromedary camels are the primary animal host for MERS-CoV (Al-Tawfiq, 2013; Chan et al., 2014; Reusken et al., 2016) . And human-to-human transmission occurs by close contacts and droplets or due to nosocomial infection (Bauerfeind et al., 2016; Sabir et al., 2016) . It is uncertain how COVID-19 transmission occurred from animals to humans. Initially, large numbers of infected people were linked to the wet animal market in Wuhan where live animals are routinely sold. So, it is suggested to be the zoonotic origin of the COVID-19. At beginning, two species of snakes identified as possible reservoir of the COVID-19. But, there is no consistent evidence of coronavirus reservoirs other than mammals and birds (Bassetti, Vena, & Giacobbe, 2020; Ji, Wang, Zhao, Zai, & Li, 2020) . Genomic sequence analysis of COVID-19 showed similarity with two bat-derived SARS-like coronaviruses (Lu, Stratton, et al., 2020; Wan, Shang, Graham, Baric, & Li, 2020) , indicating that mammals are the most likely link between COVID-19 and humans.

In the case of human-to-human transmission, the mechanism of transmission remains controversial (Chan et al., 2020; Li, Guan, et al., 2020; Phan et al., 2020) to some extent. The reports have suggested that human-to-human transmission is a likely route for spreading the novel CoV, which is supported by the cases that occurred within families or among the people who did not visit the wet animal market (Carlos et al., 2020; Wu, Hao, et al., 2020) . Human-to-human transmission occurs via direct contact or through droplets spread by coughing or sneezing from an infected individual. In some cesarean cases of pregnant women having COVID-19 positive, there was no evidence for transmission from mother to child. Hence, it is not clear whether transmission can occur during vaginal birth or not. Moreover, no evidence of in utero transmission was seen in SARS or MERS to date (Rasmussen, Smulian, Lednicky, Wen, & Jamieson, 2020) .

SARS-CoV-2 possesses spike protein, nucleocapsid protein, membrane glycoprotein, small membrane protein, and hemagglutinin esterase (Wu, Hao, et al., 2020; Zhou, Yang, et al., 2020) . The spike protein contains a 3-D structure in the RBD region to maintain van der Waals forces . The glycoprotein spikes present on the outer surface are mostly responsible for attachment and entry to the host cells ( Figure 3 ). The RBD is loosely attached among viruses, so, the virus may infect multiple hosts (Perlman & Netland, 2009; Raj et al., 2013) . SARS-CoV and MERS-CoV recognize exopeptidases as a key receptor for entry to human cells , while others mostly recognize aminopeptidases or carbohydrates. The entry mechanism of human coronavirus depends upon HAT and TMPRSS2, which splits spike protein and may establish further penetration changes (Bertram et al., 2011; Du et al., 2009) . MERS coronavirus binds DPP4, while SARS-coronavirus binds ACE2 as a key receptor Wang et al., 2013) and both are found in lung cells. Also, it is not clear whether COVID-19 is receiving ADE from other coronaviruses or not. We are at the beginning to understand the dynamics of COVID-19 in humans and its impact (Tetro, 2020) . COVID-19 infection has caused pulmonary, renal, cardiac, and circulatory damage that proves fatal in patients. Keeping in mind, Baig, Khaleeq, Ali, & Syeda, 2020 have investigated the involvement and possible contribution of neurological tissue damage to the morbidity and mortality caused by COVID-19.

A number of "unknown viral pneumonia" cases in China by a novel coronavirus (SARS-CoV-2) ; WHO, 2020c) were suddenly reported in December 2019. In just three months, this highly contagious virus has spread from Wuhan to almost all the continents. As the proper vaccination process for SARS-CoV-2 is not available, it is very important to identify it in early stage. By which immediate isolation of the infected person may be taken care from the healthy population. According to the latest guideline (trial sixth version) published by China government (General Office of National Health Committee., 2020), the diagnosis of COVID-19 should be confirmed by RT-PCR or gene sequencing for respiratory or blood specimens. Also, Chest CT is playing important role in the diagnosis of current COVID-19 detection in epidemic areas. Keeping in mind, Ai Bernheim et al., 2020 have analyzed chest CT findings in 121 infected patients in relationship to the time between symptom onset and the initial CT scan. In this study, they observed that certain CT findings are more common depending on the time course of infection. The reported chest imaging features of COVID-19 are similar with other types of CoV syndromes. Keeping in mind, Kooraki, Hosseiny, Myers, & Gholamrezanezhad, 2020 have reported the precautions and safety measures for medical staff members to manage patients with suspected NCIP. Clinical diagnosis of COVID-19 is mainly based on epidemiological history, clinical manifestations, nucleic acid detection, CT scan, POCT of IgM/IgG, ELISA, and blood culture. CoV infections led to damage the lung and may cause pneumonia. In light of this, Li, Guan, et al., 2020 have discussed the current knowledge of diagnosis, treatment and molecular immune pathogenesis for COVID-19. The combining assessment of laboratory and clinical findings could be helpful for early diagnosis of COVID-19 pneumonia (Shi, Han, et al., 2020) .

Radiologists are the first-line health care person, exposed directly to COVID-19 patients. The role of radiologists is given by Kim, 2020 . According to him, with the detection of lung abnormality, they should suggest the disease severity and possible co-infection in other hospitalized patients. Lei, Li, Li, & Qi, 2020 have discussed the CT images in a 33-year-old woman. According to their study, the bilateralism of the peripheral lung opacities, without subpleural sparing, is the common CT findings of COVID-19 pneumonia. A low-cost and disposable colorimetric PAD should be developed for simple, rapid screening and detecting in infectious diagnostics. Such alternative approach of detection for MERS-CoV has also been developed (Teengam et al., 2017) .

The ongoing epidemic of COVID-19 is becoming unstoppable and has broken all previous records and declared pandemic by WHO (Callaway, 2020 Dong, Du, & Gardner, 2020 have developed an interactive web-based dashboard to track COVID-19 in real time. This study was hosted by CSSE at Johns Hopkins University, USA, to visualize and track reported cases of COVID-19 in real time.

The Diamond Princess Cruise ship having 3,711 people was infected by SARS-CoV-2 (Ministry of Health, Labour and Welfare of Japan, 2020). A significant number of positive cases have been identified, which may be due to human-to-human transmission as there were limited space and high population density (Zhang, Diao, et al., 2020) . The novel COVID-19 is highly contagious and is transmitted mostly through respiratory droplets. But, whether its transmission can be forwarded by touching a surface (ie, a fomite) is uncertain. Hence, a thorough understanding of the virus transmission should be essential as we know the transmission of MERS-CoV occurs mainly through nonhuman, zoonotic sources (camels, bats; Mobaraki & Ahmadzadeh, 2019). The proposed transmission mechanism of human CoV is shown in Figure 4 .

Isolation of positive cases and contact tracing is used to control the outbreak. Keeping in mind, Hellewell et al., 2020 have used a mathematical model to assess whether isolation and contact tracing are really able to control the outbreak. Moreover, Rothana & Byrareddy, 2020 have reported the pathogenesis, phylogenetic analysis, epidemiology, symptoms, transmission, and future directions to control the onward transmission. The containment measures in China are successfully reducing transmission, which decreased the epidemic growth (Roosa et al., 2020) . Such reduction is not the case elsewhere, and USA, Brazil, Italy, Spain, Germany, France, Russia, and India have been affected a lot (Remuzzi & Remuzzi, 2020; WHO, 2020) . In these countries, a large number of asymptomatic carriers and mild patients may be present in the community. It is very important to identify and isolate them from healthy population . As we all know that prevention is better than cure, preventing and controlling the outbreak must be focused on the early isolation of patients and quarantine from close contacts in families and healthy population (Tian, Hu, et al., 2020) . Moreover, social distancing will play a positive effect to control the outbreak as it will decrease the community transmission.

The symptoms of novel COVID-19-infected pneumonia appear after an incubation period of ~5.2 days (Li, Guan, et al., 2020) . The common symptoms for COVID-19 are identified by fever, dry cough, headache, fatigue, anosmia, and dyspnea. But in second phase, other symptoms such as sputum production, haemoptysis, diarrhea, and | 9 MOHAPATRA eT Al. lymphopenia will be observed (Carlos et al., 2020; Ren et al., 2020; Wang, Tang, et al., 2020) . The clinical features of chest CT scan revealed pneumonia, RNAaemia, acute cardiac injury, and GGOs .

Both SARS-CoVs enter the cell via ACE2 receptor (Wan et al., 2020; Zhou, Yang, et al., 2020) . The SARS-Cov-2 first infects lower airways and binds to ACE2 (found in lung) on alveolar epithelial cells. Both viruses activate immune cells and induce the secretion of inflammatory cytokines and chemokines. The "cytokine storm" is the proposed mechanistic theory for organ damage, which leads to death . The period of death ranged from 6 to 41 days from the onset with a median of 14 days (Wang, Tang, et al., 2020) . This depends on the age and immune system of the patient.

No approved vaccines or specific treatments are yet available against SARS-CoV, MERS-CoV infection for potential therapy of humans. So many researchers are trying to develop a vaccine using a variety of platforms (Graham, Donaldson, & Baric, 2013; Kato et al., 2019; Schindewolf & Menachery, 2019) . It may take months and years to develop particular vaccines for such a rapidly mutating SARS-CoV-2 as these studies are in progress and more laboratory and clinical trials still should be explored. Furthermore, antigen presentation may be affected by CoV (Menachery et al., 2018) . According to WHO, minimum 18 months required for the development of COVID-19 vaccines (Huaxia, 2020) .

Since SARS-CoV-2 is a kind of RNA virus, so it possesses some similar functional proteins as of HIV. Hence, the HIV protease inhibitors may be effective for potential therapy of humans. Recently, lopinavir/ritonavir (LPV/r) combination has been recommended for the treatment of COVID-19 pneumonia. This combination was previously confirmed for the effective treatment of MERS-CoV and SARS-CoV (Chu et al., 2004; Momattin, Al-Ali, & Al-Tawfiq, 2019) . Baricitinib may be suggested as a potential drug for COVID-19 treatment which might reduce the process of both virus invasion and inflammation (Richardson et al., 2020) . As per molecular docking studies, another anti-HIV drug nelfinavir was anticipated to be active against SARS-CoV-2 (Xu, Peng, et al., 2020) . Remdesivir and chloroquine could inhibit COVID-19 infection in vitro . Moreover, Arbidol has a broad-spectrum antiviral activity against respiratory viruses. The clinical trials of safety and efficacy of these drugs are going on. In addition, SARS-CoV-specific human mAb (CR3022) could bind potently with 2019-nCoV receptor-binding domain (Tian, Li, et al., 2020) . So, CR3022 should be developed to prevent and treat new coronavirus infections.

It is also reported that 75 patients were treated by using 75 mg oseltamivir, 500 mg lopinavir, 500 mg ritonavir, and 0.25 g ganciclovir (intravenous) for 3-14 days Chen, Zhou, et al., 2020) . Moreover, one patient treated by lopinavir/ritonavir showed improvements in his chest radiographs after four days (Huang, Tu, et al., 2020) . This combination was also reported by Bhatnagar et al., 2020 with the protocol as per the guidelines of ICMR and WHO (WHO, 2020d) . Also, a case of COVID-19 pneumonia is responding well to remdesivir in USA, which is now undergoing a clinical trial in China (Cao, Deng, & Dai, 2020; Lai et al., 2020) . Hence, it may be used as a possible therapeutic option for COVID-19 pneumonia (Al-Tawfiq, Al-Homoud, & Memish, 2020; Ko et al., 2020) . The safety and efficacy of chloroquine for the treatment of COVID-19 are discussed by Cortegiani, Ingoglia, Ippolito, Giarratano, & Einav, 2020 . Furthermore, hydroxychloroquine may be effective in inhibiting COVID-19 infection due to less toxic nature Liu, Xiao, et al., 2020; Sivabakya & Srinivas, 2020) . Caly, Druce, Catton, Jans, & Wagstaff, 2020 have also reported recently that the anti-parasitic Ivermectin inhibits the replication of SARS-CoV-2 in vitro. The ongoing advances in designing vaccines and therapeutics to counter COVID-19 pneumonia have been highlighted by Dhama et al., 2020 . Moreover, Lin, Lu, Cao, & Li, 2020 have recommended high-doses intravenous immunoglobulin and low-molecular-weight heparin anticoagulant therapy as an effective treatment for severe and critical type patients. In addition, some recent clinical trials on drug repositioning for COVID-19 pneumonia treatment were also listed (Fisher & Heymann, 2020; Rosa & Santos, 2020) . The novel virus may damage the central nervous system of the patient (Zhou, Zhang, Wang, & Gao, 2020) . In that case, the health workers should focus on intensive care. The combined effect of hydroxychloroquine and ivermectin is also suggested by Patrì & Fabbrocini, 2020 . But there is no in vitro evidence reported on the combined effect. Moreover, sitagliptin may be useful for the patients having pre-existing cardiovascular and (or) diabetic issues (Bardaweel, Hajjo, & Sabbah, 2021) . Due to the involvement of immune hyperactivation and ARDS in fatal cases of COVID-19, anti-rheumatic drugs such as hydroxychloroquine and tocilizumab have been proposed by Zhong, Tang, Ye, & Dong, 2020 as potential therapies for the treatment of COVID-19. Triple antiviral therapy with lopinavir-ritonavir, interferon beta-1b, and ribavirin were safe and superior to lopinavir-ritonavir alone for mild to moderate COVID-19 patients (Hung et al., 2020) . In addition, Teicoplanin, an antibiotic exhibited significant efficacy to inhibit the first stage of MERS-CoV previously. Its activity may be beneficial against this novel virus (Baron, Devaux, Colson, Raoult, & Rolain, 2020) . Some existing drugs ( Figure 5 ) used against COVID-19 infection are listed in Table 3 . However, more research is urgently needed to identify novel chemotherapeutic drugs for treating and controlling COVID-19 infections. Several clinical trials are going on to assess the adequacy of therapeutic agents (Menni, Sudre, Steves, Ourselin, & Spector, 2020) . Such drugs will help to reduce the morbidity and mortality, whereas, prophylactics and vaccines will prevent further disease transmission (Park, Thwaites, & Openshaw, 2020) .

CoV is biologically diverse and rapidly mutating. So, anticoronavirus therapy is somewhat challenging. ) have designed some broad-spectrum antiviral compounds and suggested to exhibit excellent properties against MERS-CoV, SARS-CoV, and the novel BetaCoV/Wuhan/2019 as well. Łoczechin et al., 2019 have reported the antiviral activity of seven different CQDs for the treatment of human coronavirus infections. In addition, Suwannarach et al., 2020 have also studied the immunomodulatory activities of fungal bioactive compounds as potential therapeutic agents against CoV. Liu, Zhou, et al., 2020 have discussed some patents disclose methodologies for treating and preventing CoV infections, which may be applicable to COVID-19. As respiratory failure is the most important findings of COVID-19, attention should be given for critically ill patients during mechanical ventilation in hospitals (Linga, Joynta, Lipman, Constantine, & Joannes-Boyau, 2020) . Till date, more than 500 clinical trials (randomized/ non-randomized) were registered with standard of care. Other trials are also enrolling over remdesivir, IL-6 inhibitors (tocilizumab and sarilumab), stemcell therapy, convalescent plasma therapy, corticosteroids, vaccine candidates, direct-acting antiviral drugs, and traditional Chinese medicines. Most of these trials are giving comparative efficacy (Table 3 ) (Thorlund et al., 2020; Tu et al., 2020) . In addition, six vaccine candidates namely mRNA (NCT04283461), aAPC (NCT04299724), DNA (NCT04336410), a lentiviral vector (NCT04276896), chimpanzee adenoviral vector ChAdOx1 (NCT04324606), and adenoviral vector 5 (NCT04313127) have entered phase I clinical trials to assess their safety and immunogenicity (Kim, Dema, & Reyes-Sandoval, 2020) .

Although it was believed that bats and pangolins were potential hosts for SARS-CoV-2 transmission, but the origin of SARS-CoV-2 remains unclear and the evidence of transmission from animals to human is not established with certainty . As reported earlier, the initial infected individuals had a common exposure spot; Wuhan Seafood wholesale market of China, where various domestic animals, wild animals and live animals including poultry, bats, rabbits, turtles, marmots, pangolins, and snakes were sold for human consumption Ji et al., 2020; . The Chinese people are commonly consumed wild animal meat and their products due to their believed medicinal value and health promoting effects (Harypursat & Chen, 2020) . So, the host range now gets expanded and it is very essential to understand the risks to other animals and possible zoonotic transmission.

On 28 February 2020, a 17-year-old Pomeranian dog in Hong Kong had tested positive as stated by Agriculture, Fisheries and Conservation Department (AFCD) (AFCD, 2020) . The dog had initially tested negative for antibodies specific to COVID-19 as antibody formation may take 14 days or more (Almendros, 2020a) . Since then, another case was reported in a two-year-old German shepherd dog on 19 March (AFCD, 2020a (AFCD, ,2020b . In both the cases, the dogs were living in close contact with SARS-CoV-2 positive owners (American Veterinary Medical Association, 2020). After that, AFCD of Hong Kong had conducted tests on 17 dogs and 8 cats, out of which only two dogs had tested positive. Both dogs later tested negative on RT-PCR, which is the most sensitive test for the diagnosis of COVID-19 (Wang, Kang, Liu, & Tong, 2020) . This study supported human-to-animal transmission. But it is still not confirmed that dogs can transmit this virus to human beings (Almendros, 2020b ).

On 31 March, a cat had tested positive on RT-PCR from oral, nasal, and fecal samples in Hong Kong by the GHKSAR (GHKSAR, 2020). Furthermore, a cat tested positive at the University of Liège in Belgium. After this issue, Shi, Wen, et al., 2020; Shi, Han, et al., 2020 have reported an experimental infection of a number of companion and domestic animals by using two SARS-CoV-2 viruses isolated from environment and human COVID-19 patient. They confirmed that cats and ferrets are highly susceptible to COVID-19 (Li, 2020) . They also suggested that SARS-CoV-2 was transmitted in cats via respiratory droplets. Moreover, cats in Wuhan were infected with SARS-CoV-2 during the outbreak, which clearly suggested true infection in them (Zhang, Wang, Qi, Shen, & Li, 2020) . The infected cats may transmit the virus to other animals living in close contact with them (Martina et al., 2003) . The first human to nondomestic animal transmission was reported in New York City, where a tiger was surprisingly infected by a positive asymptomatic zookeeper (USDA, 2020). Hence, it is suggested that the owners should adopt appropriate precautions and keep a suitable distance from the animals to prevent the spread of this virus (Rodriguez-Morales, Dhama, Sharun, Tiwari, & F I G U R E 5 The possible drugs used against COVID-19 pneumonia Bonilla-Aldana, 2020; .

Due to the broad host range, the virus keeps on circulating between vertebrates, various animal species, and humans . The wide host range of this novel virus is believed to be due to instability of the replicase enzyme, RNA-dependent RNA polymerase, O-linked glycans, polybasic furin cleavage site, higher rate of mutations, and genetic recombination (Chen, 2020; Patel & Jernigan, 2020) . Initially, it was believed that bats or pangolins are the probable sources of origin of this novel virus (Andersen, Rambaut, Lipkin, Holmes, & Garry, 2020; Wu, Zhao, et al., 2020; . But the actual intermediate host and the nature are yet to be explored.

Basic research on SARS-CoV-2 is essential to support the process of development of the therapeutic agents. It is useful to realize some models that can authentically imitate the comportments of coronavirus and reproduce the pathology of COVID-19 (Takayama, 2020) . Here, we enumerated briefly the applicable models: cell lines, organoids, and animal models.

• Cell lines and organoids for SARS -CoV-2

The in vitro cell model can offer valuable information about the virus infection. The cell lines (Human airway epithelial, Vero E6, Caco-2, Calu-3, HEK 293T, Huh 7) and T A B L E 3 Some existing drugs for the possible use against COVID-19 organoids (human bronchial, human lung, human kidney, human liver ductal, human intestinal, human blood vessel) are a method to study the virus and the interactions inside host cells (Takayama, 2020) .

• Animal models for SARS -CoV-2

Animal models are providing significant contributions to evaluate the vaccines for a particular disease. It will help in understanding the disease process and developing prophylactics and therapeutics . The pathology of COVID-19 can be replicated and observed in a tissue-specific by using animal models. Small animals (wild-type mice, human ACE2 transgenic mice, Syrian hamsters) and large animals (ferrets, cats, Cynomolgus macaques, Rhesus macaques) are being used for evaluating vaccines and drugs against SARS-CoV-2 (Takayama, 2020; Tiwari et al., 2020) . Rhesus macaques displayed high virus amount in oral-naso and rectal swabs while working on SARS-CoV-2. In studying the pathogenesis of the disease, the apparent lesions and clinical signs contribute significantly in developing vaccines and antivirals (Munster et al., 2020) .

Golden Syrian hamsters were suggested to be the promising animal model when investigated against SARS type strains for revealing CoV pathology and pathogenesis (Roberts et al., 2008) . Furthermore, transgenic mice are now considered to be compatible model for SARS-CoV-2 but initially, mice were challenging due to the difference in receptor ACE2 usage pattern Liu, Cao, et al., 2020; Liu, Zheng, et al., 2020; Liu, Xiao, et al., 2020; Wang, Tang, et al., 2020; Zhou, Yang, et al., 2020) . On modeling cats, ferrets, pigs, orangutans, monkeys, bats, and humans are akin based on the structural similarity of their ACE2 receptors (Jarvis, 2020) . Hence, these may contribute significantly as animal models to investigate further studies.

As there are no approved vaccines or antiviral therapeutic agents for the treatment of COVID-19, the existing pieces of evidence are discussed herewith. It is suggested that immunotherapy is an efficient therapeutic option against the infected patients (Jafari & Ghasemi, 2020) . Acute respiratory distress syndrome (ARDS) can induce the apparition of other complications, including secondary bacterial infection and lung fibrosis. Recent clinical data have led to the conclusion that severe COVID-19 is determined by an over reactive immune response leading to a cytokine storm and the development of ARDS (Bonam, Kaveri, Sakuntabhai, Gilardin, & Bayry, 2020) . For severe cases, host-directed immunotherapy is an adjunct therapy to reduce inflammation and inflammation-associated lung damage and to prevent ICU hospitalization. Several immunotherapeutic strategies targeting either inflammatory mediators, or passively neutralize SARS-CoV-2, or prevent them from viral entry are under evaluation (Bonam et al., 2020; Groß, Jahn, Cushman, Bär, & Thum, 2020; Jafari & Ghasemi, 2020; Shih, Wu, Tu, & Chi, 2020) .

Till date, all immunotherapy attempts for this novel virus comprise ACE2 immunoadhesin, immunoglubolins, polypeptide hormone for maturation of T cells, a monoclonal antibody against interleukin-6 (IL-6) and polyclonal antibody by plasma therapy. Immunoglobulins and plasma therapy intervention for SARS-CoV-2 infected patients could improve clinical outcomes (Jafari & Ghasemi, 2020) . Moreover, to block the virus entry and attachment, monoclonal antibodies are preferred due to their purity, specificity, safety, low risk of blood-borne pathogen contamination (Shanmugaraj, Siriwattananon, Wangkanont, & Phoolcharoen, 2020) . ACE2 immunoadhesin has not been tested yet. Some of these methods were discussed in a clinical trial study reported by ).

Most of the COVID-19 patients were observed to have increased in IL 6, leading to lung tissue damage. The same elevated serum levels of IL-6, TNF-α, and IFN-γ were observed in cytokine release syndrome (CRS). Interleukin-6 (IL-6) acts as both anti-inflammatory myokine and pro-inflammatory cytokine. A rapid resolution of CRS symptoms in COVID-19 patients has to target either IL-6 receptor (tocilizumab, a recombinant humanized monoclonal antibody) or IL-6 (siltuximab, a chimeric monoclonal antibody) to avoid the pulmonary edema, hypotension, and cardiac dysfunction (Le et al., 2018) . Human monoclonal antibody (sarilumab), Anti-IL-6 receptor antibodies (tocilizumab), and anti-IL-6 antibody (siltuximab) are under evaluation in different centers (Baruah & Bose, 2020; Kruse, 2020; . ASCIA recommends that tocilizumab may be considered as an off-label treatment option for the patients with ARDS, and its clinical trials.

Furthermore, other interventions such as nanoparticles, viral-vectors, and corticosteroids were also suggested for SARS-CoV-2. In this contest, Liao et al., 2020 have discussed the bronchoalveolar immune microenvironment design underlying immunopathogenesis in COVID-19. Reis & Lima, 2020 have proposed a modified version of the CHA2DS2-VASc score to reduce thromboembolic complications before the condition becomes severe. WHO advised "Do not routinely give systemic corticosteroids for the treatment of viral pneumonia outside clinical trials" (WHO, 2020d). However, ASCIA supports its use because the available data were generally low quality with small patient numbers (ASCIA, 2020). In addition, Klimek et al., 2020 have suggested the allergen-specific immunotherapy (AIT) that confers a long-term clinical benefit (activates immune tolerance responses) for the diseases like allergic rhinoconjunctivitis, allergic bronchial asthma, etc. (Bousquet, Lockey, & Malling, 1998; Jutel et al., 2013) . The immune mechanisms in AIT and COVID-19 were also discussed (Klimek et al., 2020) . This report may provide ample references for the researchers to develop vaccines and antivirals against this novel emerging virus.

This manuscript has discussed various elements of COVID-19 infection and its onward transmissions. After originating from Wuhan, this zoonotic virus has spread rapidly to 213 countries and territories in the globe and causing SARS in humans, which forced to declare it "Pandemic" by WHO, as R 0 > 1. As per the laboratory confirmed positive cases, respiratory failure is the most common findings of COVID-19. But the common symptoms are dry cough, fever, headache, loss of smell or taste, muscle pain, dyspnea, diarrhea, and pneumonia. This recent outbreak believed to be originated from bats and has resulted 4,50,686 deaths as on 19 June 2020 due to human-to-human transmission. Due to this onward transmission, more than 83 lakh positive cases are found in the globe till date and still increasing rapidly. Some countries are trying to fight by preventing community transmission to control the outbreak. Due to unclear mechanism for COVID-19 transmission, it is difficult to develop evidence-based infection control protocols to prevent community transmissions. According to the latest guideline published by China government, the diagnosis of COVID-19 should be confirmed by RT-PCR or gene sequencing for respiratory or blood specimens. Furthermore, Chest CT is playing a vital role in early detection of current COVID-19 pneumonia. The clinical features of chest CT scan revealed pneumonia, RNAaemia, acute cardiac injury, and GGOs. Some patients may present normal chest finding despite of testing COVID-19 positive.

As there are no specific vaccines available against COVID-19 infection, the treatment may be carried out by using available broad-spectrum antiviral drugs like nucleoside analogues and HIV protease inhibitors. Lopinavir/ritonavir (LPV/r) combination has been recommended for the treatment. The broad-spectrum antiviral remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection. Also, the combined effect of hydroxychloroquine and ivermectin will play important rule in inhibiting 2019-nCoV infection. It is also suggested that hydroxychloroquine and azithromycin may be useful for the early treatment of patients. Another most important thing is "isolation of positive cases, contact tracing, and social distancing will be very helpful to control the outbreak". In this contest, Chu et al., 2020 have suggested that physical distancing, face masks, and eye protection to prevent person-to-person transmission. According to Hibberd, "If you can identify and quarantine most of the positive cases, then you do not have to lockdown everyone else" (Burki, 2020) . Furthermore, we may boost our immunity with Tinospora cordifolia (Guduchi) as recommended by Ayurveda, India. In addition, preventives (Arsenic album) may be used as suggested by Department of Ayush, Government of India. This review presents a strong intellectual background on the origin, transmission, symptoms, diagnosis, possible vaccines, animal models, and immunotherapy for this novel COVID-19 pneumonia, which gives an in-depth insight into several aspects of this global pandemic and will provide ample references for the researchers as well as society. Moreover, the information's included in this review may be useful for the ongoing development of therapeutic agents and vaccines and also preventing the spread of this disease.

The authors are highly thankful to the editor and reviewers for their valuable and constructive suggestions to modify the manuscript. RKM is also thankful to Principal, Government College of Engineering, Keonjhar, for his help and facilities.

The authors declare that they have no conflicts of interest in this work.

Not applicable.

https://orcid. org/0000-0001-7623-3343 Lucia Pintilie https://orcid.org/0000-0002-1036-7653

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