139 International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 Review article: Review of the Corona Viruses Causing Acute Respiratory Syndrome and COVID-2019 (COVID-19) Pandemic AN Alam1 M Siddiqua2, Al-Mahmood AK3, Aminur Rahman4 Abstract: A new virus, Severe Acute Respiratory Syndrome Corona Virus-2 (SARS CoV-2) emerged in December 2019 and still continuing to pose a great threat all over the Globe claiming to a fatality 980,031 persons. Among the human corona viruses it is the third one causing acute respiratory distress syndrome. The others two are SARS CoV and MERS CoV. The objective of this study is to review the human corona viruses causing severe respiratory distresses which are detected thru analysis of some recently published documents on the deadly SARS CoV-2 as well as information on SARS-CoV and MERS CoV from different world class trust worthy reliable and dependable sources. Genetic analysis reveals that the new human corona virus (SARS CoV-2) has similarities with the severe acute respiratory syndrome like (SARS like) bat virus which thought to be the primary reservoir. SARS- CoV and MERS-CoV also have same bat reservoir but the intermediate host are different for three human corona viruses. Though the clinical picture is more or less similar but efficiency of human to human transmission is not same for these viruses. So, strict control measures are critical to contain this very big pandemic been occurring since December 2019. Everyday new information has been coming causing strategy to change to control this pandemic. Zoonotic origin of corona viruses indicate researchers, public health specialists should keep the continuous surveillance for early detection of new virus alike SARS –CoV-2. Keywords: Corona virus, SARS-CoV, MERS-CoV, Covid-19, Outbreak, Pandemic, Correspondence to: Dr. Ahmed Nawsher Alam, Principal Scientific Officer, Institute of Epidemiology, Disease Control & Research, Government of the Peoples’ Republic of Bangladesh (GoB), Mohakhali, Dhaka 1212. Email: anawsher@yahoo.com 1. Dr. Ahmed Nawsher Alam, Principal Scientific Officer, Institute of Epidemiology, Disease Control & Research (IEDCR), Government of the Peoples’ Republic of Bangladesh (GoB), Mohakhali, Dhaka 1212 Email: anawsher@yahoo.com 2. Dr. Mahmuda Siddiqua, Professor (CC), Department of Microbiology, Ibn Sina Medical College & Hospital, Kallyanpur, Dhaka 1216 E-mail: mahmuda99@yahoo.com 3. Professor Abu Kholdun Al-Mahmood, Professor & Head, Department of Biochemistry, and Vice-Principal, Ibn Sina Medical College, Kallyanpur, Mirpur, Dhaka 1216, Email:kholdun@hotmail.com 4. Aminur Rahman, Former Manager, icddr,b, Mahakhali, Dhaka 1212, Email: rahman55aminur@gmail.com International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 Page : 139-147 DOI: http://dx.doi.org/10.31344/ijhhs.v5i2.250 Introduction: In last December 2019, an acute respiratory Corona Virus Disease (COVID-19), caused by the novel corona virus (SARA-CoV-2) was identified first in the Wuhan of China and received immediate worldwide attention. The World Health Organization (WHO) named this corona virus initially as the novel corona virus 2019 (2019-nCoV). Later, the Corona Virus Study Group (CSG) of the International Committee proposed the name of new corona virus as SARS-CoV-21 and WHO officially accepted the disease as Corona Virus Disease 2019 (COVID-2019)2. The Chinese scientists very fast isolated the new virus SARS-CoV-2 from an infected patient within a very short possible time and done genome sequencing3. The WHO officially declared COVID-19 pandemic as a public health emergency of international concerns on 30 January 2020. As of International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 140 25 September 2020, a total of 32,110,656 cases were confirmed as infected by the COVID-19 globally including 980,031 deaths where as in Bangladesh, 356,767 COVID-19 positive cases were detected including 5,093 deaths4. The emergence of SARS-CoV-2 considered as the third high pathogenic and large-scale epidemic corona virus into the human beings in twenty- first century, since the outbreak of severe acute respiratory syndrome corona virus (SARS- CoV) in 20025 and the Middle East respiratory syndrome corona virus (MERS-CoV) in 2012. The basic reproduction number (noted as the R0) of SARS-CoV-2 was reported to be around 2.26 or even more range from 1.4 to 6.57. Cluster of the pneumonia outbreaks within the families indicates steady human to human transmission of the pandemic COVID-19 worldwide8. Corona Virus: The Corona Viruses (CoVs) belong to the family Coronaviridae, which is the largest family within the order Nidovirales Orthocoronavirinae and Torovirinae are two subfamilies of the Coronaviridae family where Orthocoronavirinae includes four genera: alpha (α)-coronavirus, beta (β)-coronavirus, gamma (γ)-coronavirus, and delta (δ)-coronavirus9. Many corona viruses are significant for the animal health threats. The first description of corona virus came from the veterinarian in 1931 which was named as ‘Infectious Bronchitis Virus (IBV) of Chickens’10. CoVs are then found in mammals, birds, camels, cattle, cats, bats, and other animals. Alpha (α) and Beta (β) corona viruses are found to be circulating in the mammals including bats, whereas γ coronaviruses are found mainly in the avian species including few mammalian species, and δ coronaviruses are detected in the birds and mammals11. Evidence shows that the animals CoVs can infect human beings rarely and could attain the ability to spread through the human-to- human transmission12. Among different human corona viruses (HCoVs) CoV-229E and CoV- OC43, cause the common cold in the humans13. Several other HCoVs were revealed in different period after emergence of those two HCoVs. Severe Acute Respiratory Syndrome-CoV (SARS- CoV) was discovered in 2002, HCoV-NL63 in 2004, HCoV-HKU1 in 2005, and the Middle East Respiratory Syndrome-CoV (MERS-CoV) in 201214. The novel CoV virus2019 (2019-nCoV) which is recently named SARS-CoV-2 is seventh human corona virus detected in China1. Fig-1: Classification of Corona Viruses Corona virus structure and entry in the host cell: Corona viruses are the spherical enveloped virus with a positive-sense single-stranded RNA genome where the spike proteins on envelope showed appearance of crown under microscope led to the name “corona virus”, a Latin word means ‘The Crown’15. The viral structures found primarily of structural proteins such as spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins, and hemagglutinin-esterase (HE) protein in the some β-corona viruses. The S, M, and E proteins are all embedded in viral envelope. However, N protein is located in the core of the viral particle16. Fig-2: Corona virus structure Spike (S) of protein of the virus is sole responsible for entry of CoVs into the host cells17. Within S-1 domain, the receptor-binding domain (RBD) binds with receptor of the host cell and S-2 domain causes the fusion between the host cell membrane and the viral envelope, required for viral entry into the host cells18,19. Several cellular receptors were found for different CoVs. For an example, amino- peptidase N (APN) receptor was identified for several α-corona viruses,20 angiotensin-converting the enzyme 2 (ACE2) receptor for SARS-CoV,21 HCoV- NL63,22 and newly discovered SARS- CoV-2,23 and dipeptidyl-peptidase 4 (DPP4) receptor for MERS-CoV24. 141 International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 Genomic Organization: The genome of CoVs including recently evolved SARS CoV-2 is the largest among all human beings RNA viruses which range from 26 to 32 kilobases (kb) in size25. The genome codes for the nonstructural and structural proteins26. The genome for CoVs comprises of the 5'-untranslated region (5'-UTR), the open reading frame (ORF), non-structural proteins (NSP) for replication, structural proteins including the spike (S), envelop (E), membrane (M), and nucleocapsid proteins (N), accessory proteins such as ORF 3, 6, 7a, 7b, 8 and 9b in the CoVs genome, and the 3'-untranslated region (3'-UTR)27. The ORF 1 translates two poly-proteins, pp1a and pp1ab, and encodes 16 non-structural proteins (NSP) which comprise about two-thirds of the whole genome, while the remaining ORFs encode accessory and structural proteins. The rest one-third of the genome encodes four essential structural proteins, which includes the spike(S) glycoprotein, small envelope (E) protein, membrane protein (M) and the nucleocapsid (N) protein28. Origin and evolution of SARS CoVs There is a long history of the cross-species transmission of CoVs29. SARS-CoV has been thought to be originated from the Chinese wet market where it crosses the species barrier from Chinese horseshoe bats through an intermediate species palm civet and the raccoon dogs to the human beings30. A lot of studies have proved that the bats and other small animals harbor SARS- related CoVs (SARSr-CoVs) that might be ancestral to the SARS-CoV in humans31. It was found that SARS-CoV has been circulating for a long time in bats before the genetic modification and jumping to humans. This genetic modification leads to adaptation SARS-CoV to the bind human ACE2 as a receptor and efficiently infect human cells32. MERS-CoV is highly related particular to two bat corona viruses, HKU4 and HKU5, identified previously33. Detection of the MERS-related CoVs (MERSr-CoVs) in bats indicates a potential bat origin34,35 but likely had an intermediate host. Studies have identified that the camel MERS-CoV strains are almost identical to human MERS-CoV strains36 which could be the intermediate host. RBD of MERSr-CoVs’ share only 60% – 70% sequence identity with that of the human and camel MERS- CoVs37. For adaptation in the human host, MERSr- CoVs had to undergo several amino acid changes in the RBD of S-protein to become capable of infecting the camels and humans38. This amino acid changes might lead to the emergence of MERS- CoV strains that enable to bind to the human DPP4 with high affinity and infecting the humans. The early cases of SARS-CoV-2 pneumonia indicate that many cases have been exposed to the Huanan Seafood Market in Wuhan, Hubei province of China39. The Genetic Analyses of the viral samples from the patients with SARS- CoV-2 infections revealed that the SARS-CoV-2 shares 79.5% nucleotide (nt) identity with SARS CoV, only 50% identity to MERS-CoV and 96% identity with the bat-CoV-RaTG1340,41. It indicates that SARS-CoV-2 is new virus that is distinct from SARS-CoV and MERS-CoV but might have a bat origin, similar to SARS-CoV and MERS-CoV41. The Huanan Seafood Market was trading variety of live animals such as the snakes, marmots, badger, hedgehog, and birds, probably pangolin but not the bats42,43 suggests that bats have less chance to direct contact with the human and direct transmission of the virus from bat to human is less likely44. Therefore, like SARS CoV and MERS CoV there may be an intermediate host in the market transmitting the virus to a human. Recently SARS CoV-2 has been isolated from pangolins, genetic sequences of which showed 99% identity with that SARS CoV-2 in humans. Now, it has been thought that transmission and evolution path of SARS CoV-2 was from bat-CoV to pangolins (intermediate host), from where it transmits to human45. Comparison between SARS-CoV, MERS-CoV, and the Newly Discovered SARS-CoV-2: The pandemic potential human corona viruses started to cause the Severe Acute Respiratory Syndrome (SARS) in humans in 2002-2003. That outbreak initiated in the Guandong area in China, Fig-3: Genome of SARS CoV-2 International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 142 and resulted in 774 deaths out of a number of 8,098 cases over the nine months period with about 10% fatality46. The un-ciliated bronchial epithelial cells and the type II pneumocytes were infected and resulted in fever, cough, shortness of breathing, and severe complications such as pneumonia and kidney failure ailments21,46. The Incubation Period for the SARS-CoV was observed for 2 to 14 days47. In 2012, another new CoV detected in Saudi Arabia that causes a severe respiratory disease named MERS-CoV48. MERS-CoV caused a similar type of clinical features as that of SARS-CoV. The incubation period of MERS-CoV is quite similar to SARS-CoV and ranging from 2 to 14 days49. Since 2012, 862 patients died out of a total 2,506 infected cases in 27 countries with a case fatality about 35%, which is more than three times than that of the SARS-CoV infections50. The third identified human Corona virus is SARS- CoV which causes the respiratory symptoms with the severe disease. It was isolated and sequenced from the patients that showed symptoms of respiratory illness and pneumonia in Wuhan in China during December 2019 51. Incubation period is the same as SARS-CoV and MERS-CoV infections39,52. Similar to SARS-CoV and unlike MERS-CoV, human-to-human transmission was confirmed41. The Respiratory Symptoms include fever, dry cough, respiratory distress, and in severe case pneumonia. The mortality seems to be caused by Acute Respiratory Distress Syndrome (ARDS)53 usually associated with comorbidities and followed by multiple organ failures leading to death. Education from outbreak of SARS-CoV, MERS-CoV, and SARS-CoV-2: Alpha (α)-corona virus (HCoV-229E, & HCoV- NL63) and β-coronavirus (HCoV-OC43 and HCoV-HKU1) have been known to cause mild, self-limiting respiratory infections with symptoms of the common cold in a human before the outbreak of SARS-CoV. The severe form of the acute respiratory syndrome was found to be caused by SARS-CoV, MERS-CoV, and very recently SARS-CoV-2, all are β-corona virus55. The diversity of corona-viruses reflects the fact that this family of viruses has an RNA dependent RNA polymerase with the poor fidelity56, and high frequency of RNA mutation57, and also easy transmission from one species to another12,58; all these factors may contribute to severe respiratory outbreaks in the human. Corona viruses that cause severe respiratory diseases have come from ancestral CoVs harbored by the bats (Fig- 3) whereas animals function as intermediate hosts (civets, raccoon dogs, camel, pangolin etc.), and the humans served as terminal hosts. In China, the live animals are sold mainly for food items or medicine at most of the wet markets. The wildlife and/or parts from the rare animals Fig-3: Diagram of origin of corona viruses 143 International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 (such as the pangolin scales and paws from a tiger) used for medicine or the magical purpose in China59. But it is to be noted that most of these folk remedies are not prescribed by the Traditional Chinese Medicine (TCM) hospitals. The Wuhan market also involved with selling of several exotic animals and their parts41. Thus, SARS-CoV-2 disease can be considered a zoonotic disease that initially spread from animals to the humans then human-to-human transmission also confirmed60. It is found that new CoVs causing outbreaks repeatedly, evolved in China. The cause for this repeated occurrence of these outbreaks is not at all well understood. Although, it can be assumed that those viruses may be predominantly circulating in the animals in China rather than animals of the world. One of the reasons could be the close interactions with live and the wild animals in the wholesale food market in China54 and the practice of eating raw meat. Such a pandemic outbreak like the COVID-19 is a concern for public health specialists to understand the magnitude of the pandemic where basic reproduction number which is known as the R0 is an important indicator61. This number measures the potentiality of the disease which represents average number of healthy people infected from an infected person in a population. The mean estimate of R0 was found in a study between 2.24 and 3.5862 and in another study with the high average value of R0 was found to be 2.5 63 which is consistent with a report from the other groups ranged from 2 to 364-66. The R0 estimates for the SARS-CoV-2 are consistent with the SARS- and MERS-CoVs ranging from 2 to 567,68. The R0 above 1(one) should always be taken seriously. The target should be to reduce the R0 below 1. An important point here is R0 estimates can vary from the “true” R0 values if the infected people remain asymptomatic or do not report their symptoms to the authority57. Conclusion: In any sorts of natural disaster, the people come together to get rid of that disaster whereas outbreaks of highly contagious infectious diseases divide the people to prevent the spreading of viruses. But viruses cross from country to country irrespective of borders and move from birds to an animal to the human. So, controlling such a pandemic outbreak requires an active and prompt international efforts and cooperation. The climate change, changes in ecology, continuous invasion of natural habitats of the animals by human for food and shelter, advanced practices in agriculture lead the wildlife to come to the human habitat which causes spillover of viruses from natural host to human. Even in this huge advancement of science, invisible viruses have been found to have devastating effects on human beings. Thus SARS-CoV, MERS-CoV, H5N1, H7N9, Ebola, and very recent COVID-19 outbreaks give an alarm to the world for the future pandemic threats by any other novel virus. Researchers should have continuous efforts and the surveillance to reduce the probability of occurrence of new infections through the sustainable investigation of animal etiology, keep strict bio-security of the high-risk pathogens, control of the wildlife trading, and decreasing direct contact with wildlife and thus control the transmission of naïve virus to human. Conflict of interest: None Source of Fund: Nil Ethical Clearance: Not Applicable Authors Contribution: Data gathering and idea owner : AN Alam Writing and editing final draft: All authors. International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 144 Reference: 1. A G Gorbalenya, S C Baker, R S Baric, et al., The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol (2020), https://doi. org/10.1038/s41564-020-0695-z. 2. Novel Corona virus (2019-nCoV) Situation Report–22, World Health Organization, 2020 Available at: https://www.who.int/docs/default source/coronaviruse/situation-reports/20200211- sitrep-22-ncov.pdf (Accessed 12 February 2019). 3. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395 (10224) : 565– 574. doi : 10.1016/S the 0140-6736 (20) 30251-8. 4. https://www.who.int/emergencies/diseases/novel- coronavirus-2019. Accessed on 25.09.2020 5. Yan-Rong Guo, Qing-Dong Cao, Zhong-Si Hong, Yuan-Yang Tan, Shou-Deng Chen, Hong- Jun Jin, et al.The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil Med Res. 2020; 7: 11. 6. Riou J, Althaus CL. Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Euro Surveill. 2020; 25(4):2000058. doi : 10.2807/1560- 7917.ES.2020.25.4.2000058. 7. Liu Y, Gayle AA, Wilder-Smith A, Rocklov J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. J Travel Med. 2020. 10.1093/jtm/taaa021. 8. Chan J F, Yuan S, Kok K H, To K K, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet.2020; 395(10223):514–523. doi: 10.1016/S0140-6736 (20) 30154-9. 9. Woo P C, Huang Y, Lau S K, Yuen KY. Coronavirus genomics and bioinformatics analysis. Viruses 2010,2, 1804–1820. 10. O. Seifried. Histopathology of Infectious Laryngo- tracheitis in chicken. J. Exp. Med. 1931, 54 (6), 817- 826. 11. Woo P C, Lau S K, Lam CS, Lau CC, Tsang A K, Lau J H, et. al. Discovery of seven novel Mammalian and avian coronaviruses in the genus delta-coronavirus supports bat coronaviruses as the gene source of alpha-coronavirus and beta-coronavirus and avian coronaviruses as the gene source of gamma- coronavirus and delta-coronavirus. J. Virol. 2012, 86, 3995–4008. 12. Forni D, Cagliani R, Clerici M, Sironi M. Molecular Evolution of Human Corona virus Genomes. Trends Microbiol. 2017, 25, 35–48. 13. Milek J, Blicharz-Domanska K. Corona viruses in Avian Species-Review with Focus on Epidemiology and Diagnosis in Wild Birds. J. Vet. Res. 2018, 62, 249–255. 14. van der Hoek, L. Human coronaviruses: What do they cause? Antivir. Ther. 2007, 12, 651–658. 15. Neuman B W, Adair B D, Yoshioka C, Quispe J D, Orca G, Kuhn P, et. al. Supra molecular architecture of severe acute respiratory syndrome corona virus revealed by electron cryo-microscopy. J. Virol. 2006, 80, 7918–7928. 16. Fehr A, Perlman S. Corona viruses: An overview of their replication and pathogenesis. Methods Mol. Biol. 2015, 1282, 1–23. 17. Hofmann H, Hattermann K, Marzi A, Gramberg T, Geier M, Krumbiegel M, et. al. S protein of severe acute respiratory syndrome-associated coronavirus mediates entry into hepatoma cell lines and is targeted by neutralizing antibodies in infected patients. J. Virol. 2004,78, 6134–6142. 18. Simmons G, Reeves J D, Rennekamp A J, Amberg S M, Piefer A J, Bates P, et al. Characterization of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) spike glycoprotein-mediated viral entry. Proc. Natl. Acad. Sci. USA 2004, 101, 4240– 4245. 19. He Y, Li J, Du L, Yan X, Hu G, Zhou Y, et al. Identification and characterization of novel neutralizing epitopes in the receptor-binding domain of SARS-CoV spike protein: Revealing the critical antigenic determinants in inactivated SARS-CoV vaccine. Vaccine 2006, 24, 5498–5508. 20. Reguera J, Santiago C, Mudgal G, Ordono D, Enjuanes L, Casasnovas J M. Structural bases of coronavirus attachment to host amino-peptidase N and its inhibition by neutralizing antibodies. PLoS Pathog. 2012, 8, e1002859. 21. Li W, Moore M. J, Vasilieva N, Sui J, Wong S K, Berne M A, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003, 426, 450–454. 22. Hofmann H, Pyrc K, van der Hoek L, Geier M, Berkhout B, Pohlmann, S. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc. Natl. Acad. Sci. USA 2005, 102, 7988–7993. 23. Wan Y, Shang J, Graham R, Baric R S, LiF. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of 145 International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 SARS. J. Virol. 2020. 24. Raj V S, Mou H, Smits S L, Dekkers D H, Muller M A, Dijkman R, Muth D, Demmers J A, Zaki A, Fouchier R A, et al. Di-peptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013, 495, 251–254. 25. Lai M M. Corona virus: Organization, replication and expression of genome. Annu. Rev. Microbiol. 1990,44, 303–333. 26. Masters P.S. The molecular biology of corona viruses. Adv. Virus Res. 2006, 66, 193–292. 27. Muhammad Adnan Shereen, Suliman Khan, AbeerKazmi, Nadia Bashir, RabeeaSiddique. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. Journal of Advanced Research 24 (2020) 91–98 28. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019; 17 (3) : 181–92. 29. Perlman S, Netland J. 2009. Coronaviruses post- SARS: update on replication and pathogenesis. Nat. Rev. Microbiol. 7: 439–450 30. Graham R L, Baric R S. 2010. Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. J. Virol. 84: 3134–3146 31. Li W, Shi Z, Yu M, Ren W, Smith C, Epstein J H, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science 2005, 310, 676–679. 32. Li W, Zhang C, Sui J, Kuhn J H, Moore M J, Luo S, et al. Receptor and viral determinants of SARS- coronavirus adaptation to human ACE2. EMBO J. 2005, 24, 1634–1643. 33. Van Boheemen S, de Graaf M, Lauber C et al. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 3. doi:10.1128/mBio.00473-12 34. Lau S K, Li K S, Tsang A K, Lam C S, Ahmed S, Chen H,et al. Genetic characterization of Betacoronavirus lineage C viruses in bats reveals marked sequence divergence in the spike protein of Pipistrellus bat corona virus HKU5 in Japanese pipistrelle: Implications for the origin of the novel Middle East respiratory syndrome coronavirus. J. Virol. 2013, 87, 8638–8650. 35. Memish Z A, Mishra N, Olival K J, Fagbo S F, Kapoor V, Epstein J H, et al. Middle East respiratory syndrome corona virus in bats, Saudi Arabia. Emerg. Infect. Dis. 2013, 19, 1819–1823. 36. Haagmans B L, AlDhahiry S H, Reusken C B, Raj V S, Galiano M, Myers R, et al. Middle East respiratory syndrome corona virus in dromedary camels: An outbreak investigation. Lancet Infect. Dis. 2014, 14, 140–145. 37. Lau S K P, Zhang L, Luk H K H, Xiong L, Peng X, Li K S M, et al. Receptor Usage of a Novel Bat Lineage C Betacorona virus Reveals Evolution of Middle East Respiratory Syndrome-Related Coronavirus Spike Proteins for Human Di-peptidyl Peptidase 4 Binding. J. Infect. Dis.2018, 218, 197–207. 38. Zhang Z, Shen L, Gu X. Evolutionary Dynamics of MERS-CoV: Potential Recombination, Positive Selection and Transmission. Sci. Rep. 2016, 6, 25049 39. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020. 40. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020. https://doi.org/ 10.1038/s41586-020-2012-7. 41. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterization and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020, 395, 565–574. 42. Wu F, Zhao S, Bin Y, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature 2020. https:// doi.org/10.1038/s41586-020-2008-3 43. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020. . 44. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019; 17: 181e92. 45. Jin-Yan Li, Zhi You, Qiong Wang, Zhi-Jian Zhou, Ye Qiu, Rui Luo, Xing-Yi Ge. The epidemic of 2019-novel-coronavirus (2019-nCoV) pneumonia and insights for emerging infectious diseases in the future. https://doi.org/10.1016/j. micinf.2020.02.002 46. Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, et al. Identification of a novel coronavirus in patients with the severe acute respiratory syndrome. N. Engl. J. Med. 2003, 348, 1967–1976. 47. Chan-Yeung, M.; Xu, R.H. SARS: Epidemiology. Respirology 2003, 8, S9–S14. 48. Zaki A M, van Boheemen S, Bestebroer T M, Osterhaus A D, Fouchier RA. Isolation of a novel corona virus from a man with pneumonia in Saudi Arabia.N.Engl.J.Med.2012, 367, 1814–1820. 49. Arabi Y M, Balkhy H H, Hayden F G, Bouchama A, Luke T, Baillie J K, et al. Middle East Respiratory Syndrome. N. Engl. J. Med. 2017, 376, 584–594. 50. Killerby M E, Biggs H M, Midgley C M, Gerber S International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 146 I, Watson J T. Middle East Respiratory Syndrome Coronavirus Transmission. Emerg. Infect. Dis. 2020, 26, 191–198. 51. Zhou P. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. Nature. 2020 52. Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, Wallrauch C, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N. Engl. J. Med. 2020. 53. Zhu N, Zhang D, Wang W. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 2020;382(8):727–733. 54. Chen N., Zhou M., Dong X. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395 (10223) : 507– 513 55. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497e506 56. One Health. Editorial: The novel Corona virus (SARS-CoV-2) is one health issue. https://doi. org/10.1016/j.onehlt.2020.100123 57. Dolan P T, Whitfield Z J, Andino R. Mechanisms and Concepts in RNA VirusPopulation Dynamics and Evolution. Annu. Rev. Virol. 2018, 5, 69–92. 58. Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 2016, 24, 490–502. 59. Hossam M A Shour, Walid F Elkhatib, Md Masudur Rahman, Hatem A Elshabrawy. Insights into the Recent 2019 Novel Coronavirus (SARS- CoV-2) in Light of Past Human Coronavirus Outbreaks. Pathogens 2020, 9,186; doi :10.3390/ pathogens9030186 60. Chan J F, Yuan S, Kok K H, To K K, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person- to-person transmission: A study of a family cluster. Lancet 2020, 395, 514–532. 61. Delamater P L, Street E J, Leslie T F, Yang Y T, Jacobsen K H. Complexity of the Basic Reproduction Number (R0). Emerg. Infect. Dis. 2019, 25, 1–4. 62. Zhao S, Lin Q, Ran J, Musa S S, Yang G, Wang W, et al. Preliminary estimation of the basic reproduction number of novel corona virus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Int. J. Infect. Dis. 2020, 92, 214–217. 63. Read J M B Jr, Cummings DA, Ho A, Jewell CP. Novel coronavirus 2019-nCoV: Early estimation of epidemiological parameters and epidemic predictions. MedRxiv2020. 64. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020. 65. Riou J, Althaus C L. Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Eurosurveillance 2020, 25, 2000058. 66. Wu J T, Leung K, Leung G M. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modeling study. Lancet 2020. 67. Lipsitch M, Cohen T, Cooper B, Robins J M, MaS, James L, et al. Transmission dynamics and control of severe acute respiratory syndrome. Science 2003, 300, 1966–1970. 68. Lin Q, Chiu A P, Zhao S, He D. Modeling the spread of Middle East respiratory syndrome corona virus in Saudi Arabia. Stat Methods Med Res 2018, 27, 1968– 1978.Se is as nobitas dolorit erum arcim sed quundae omnim quasped min plam fugitatem volum 147 International Journal of Human and Health Sciences Vol. 05 No. 02 April’21 pancreatic ductal adenocarcinoma and chronic pancreatitis using multimarker expression data and samples obtained by minimally invasive fine needle aspiration. Int J Cancer. 2007 Jan 30,120(7):1511–7. 32. de Geus SWL, Boogerd LSF, Swijnenburg R-J, Mieog JSD, Tummers WSFJ, Prevoo HAJM, et al. Selecting Tumor-Specific Molecular Targets in Pancreatic Adenocarcinoma: Paving the Way for Image-Guided Pancreatic Surgery. Mol Imaging Biol. 2016/04/29. 2016,18(6):807–19. 33. Gorantla B, Asuthkar S, Rao JS, Patel J, Gondi CS. Suppression of the uPAR–uPA System Retards Angiogenesis, Invasion, and In Vivo Tumor Development in Pancreatic Cancer Cells. Mol Cancer Res. 2011 Apr 1,9(4):377 LP – 389. 34. Hamada S, Shimosegawa. T. Pancreatic cancer stem cell and mesenchymal stem cell. In: Grippo PJ, Munshi HG, editors. Pancreatic Cancer and Tumor Microenvironment. Trivandrum: Transworld Research Network, 2012. p. 111–22. 35. Asuthkar S, Stepanova V, Lebedeva T, Holterman AL, Estes N, Cines DB, et al. Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer. Mol Biol Cell. 2013 Sep 1,24(17):2620–32. 36. Khanna A, Mahalingam K, Chakrabarti D, Periyasamy G. Ets-1 expression and gemcitabine chemoresistance in pancreatic cancer cells. Cell Mol Biol Lett. 2011,16(1):101–13. 37. Gendronneau G, Lemieux M, Morneau M, Paradis J, Têtu B, Frenette N, et al. Influence of Hoxa5 on p53 tumorigenic outcome in mice. Am J Pathol. 2010 Feb,176(2):995–1005. 38. Shi H, Sun M, Liu L, Wang Z. Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects. Mol Cancer. 2014,13(1):1. 39. Norelli M, Casucci M, Bonini C, Bondanza A. Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects. Biochim Biophys Acta (BBA)- Reviews Cancer. 2016,1865(1):90–100. 40. Mirzaei HR, Rodriguez A, Shepphird J BC. Chimeric Antigen Receptors T Cell Therapy in Solid Tumor : Challenges and Clinical Applications. Front Immunol. 2017,8(1850):1–13. 41. Cartellieri M, Bachmann M, Feldmann A, Bippes C, Stamova S, Wehner R et al. Chimeric antigen receptor-engineered T cells for immunotherapy of cancer. Biomed Res Int. 2010,2010:956304. 42. Zhang C, Liu J, Zhong JF ZX. Engineering CAR-T cells. Biomark Res. 2017,5(22):3–8. 43. Xu X-J TY-M. Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells. Cancer Lett. 2014,343(2):172–8. 44. Lee DW, Stetler-Stevenson M, Yuan CM, Fry TJ, Shah NN, Delbrook C et al. Safety and response of incorporating CD19 chimeric antigen receptor T cell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia. Am Soc Hematol. 2015,126(23):684. 45. Arcangeli S, Magnani CF, Tettamanti S BE. Switchable chimeric antigen receptor T cells: a novel universal chimeric antigen receptor platform for a safe control of T-cell activation. Transl Cancer Res. 2016,5(12):174–7. 46. Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR et al. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci. 2016,113(4):459– 68. 47. Therapies A, Arbor A. Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells. Br J Haematol. 1998,103:110–23. 48. Zhang E, Xu H. A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy. J Hematol Oncol. 2017,10(1):1. 49. Gao N, Bozeman EN, Qian W, Wang L, Chen H, Lipowska M, et al. Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery. Theranostics. 2017,7(6):1689–704. 50. Warheit DB, Sayes CM, Reed KL, Swain KA. Health effects related to nanoparticle exposures: Environmental, health and safety considerations for assessing hazards and risks. Pharmacol Ther. 2008,120(1):35–42. 51. Imam SZ, Lantz-McPeak SM, Cuevas E, Rosas- Hernandez H, Liachenko S, Zhang Y, et al. Iron Oxide Nanoparticles Induce Dopaminergic Damage: In vitro Pathways and In Vivo Imaging Reveals Mechanism of Neuronal Damage. Mol Neurobiol. 2015,52(2):913–26. 52. Yarjanli Z, Ghaedi K, Esmaeili A, Rahgozar S, Zarrabi A. Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci. 2017,18(1):51.