key: cord-1050516-o1mrpgvj authors: Hemmati-Dinarvand, Farshad; Saedi, Samira; Hemmati-Dinarvand, Mohsen; Zarei, Marzie; Seghatoleslam, Atefeh title: Mysterious Virus: A Review on Behavior and Treatment Approaches of the Novel Coronavirus, 2019-nCoV date: 2020-05-06 journal: Arch Med Res DOI: 10.1016/j.arcmed.2020.04.022 sha: 85d73990364ff7ca2c8c4876980835274d72c58b doc_id: 1050516 cord_uid: o1mrpgvj Abstract At the end of the year 2019, the novel coronavirus (2019-nCoV) was spreading in Wuhan, China, and the outbreak process has a high speed. It was recognized as a pandemic by the World Health Organization (WHO) on 11 March 2020. Coronaviruses are enveloped and single-stranded RNA that have several families including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The pathogenesis mechanism and disease outcomes of SARS and MERS are now clear to some extent, but little information is available for 2019-nCoV. This newly identified corona virus infection represents flu-like symptoms, but usually the first symptoms are fever and dry cough. There has been no specific treatment against 2019-nCoV up to now, and physicians only apply supportive therapy. In the present article, we made an attempt to review the behavior of the virus around the world, epidemiology, a pathway for influx into the host cells, clinical presentation, as well as the treatments currently in use and future approaches; nitazoxanide may be our dream drug. We hope that this review has a positive impact on public knowledge for helping to deal with the 2019-nCoV and move one step forward toward its treatment in the near future. In late 2019, the local health authorities in Wuhan, China, declared a high load of individuals that had pneumonia with unknown etiology (1) . Subsequently, in early January 2020, numerous medical diagnostic laboratories in China reported that a new coronavirus was the cause of occult pneumonia. The World Health Organization (WHO) named this invasive virus briefly as 2019 novel coronavirus (2019 nCoV) (2) . Coronaviruses are enveloped, single stranded RNA, and belong to the subfamily Coronavirinae. It has previously been reported that CoVs which causes human diseases have six types, and is categorized into two subgroups including gently and extremely pathogenic CoVs. The 229E, HKU1, OC43 and NL63 are gently pathogenic CoVs, leading to 10-30% of upper respiratory tract infections (3, 4) . Instead, the extremely pathogenic CoVs, containing Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), mostly contaminate lower airways and lead to pneumonia (5) . Given that the clinical signs of2019 nCoV, SARS CoV, and MERS CoV have some resemblances, it can range from asymptomatic infections to severe respiratory illnesses (6) . The rapid prevalence of the novel type of CoV reminds us that it is a major global health threat. Chen Y, et al. think that severe prevalence of novel CoV in the future is inevitable as climate is changing and human exposure to animals is increasing; therefore, the need for effective treatment modalities and training for CoVs is necessary (2) . In the present article, we attempted to review the behavior of the virus around the world, epidemiology, a pathway for influx into the host cells, clinical presentation, as well as the treatments currently in use. We hope that this review could have a positive impact on our knowledge of the new virus and help establish effective ways to combat the novel coronavirus 2019 in near future. Coronaviruses (CoVs) form a large and important family of viruses found in nature. CoVs have a positive-sense single-stranded RNA (+ssRNA) with a GC content of 32-43% that belongs to the family Coronaviridae and the order Nidovirales. They contain the largest genome among the recognized RNA viruses (genome length is about 26-32 kb) (7) . Based on the genomic structure and phylogenetic analysis, the family Coronaviridae is currently classified into two subfamilies, Sarbecovirus containing SARS-CoV are two major zoonotic pathogenic coronaviruses (Table 1) . Anew pandemic Coronavirus, so called 2019-nCoV, has been recently introduced in Wuhan, China (11) . 2019-nCoV is still considered as unclassified Betacoronavirus, but according to early phylogenetic studies, this virus is related to SARS and is over 85% matched with the bat SARS-like CoV (9) . Accordingly, the International Committee on Taxonomy of Viruses named it severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The 2019-nCoV is an enveloped, spherical, and relatively large (about 120 nm in diameter) particle; the envelope of this virus in electron micrographs emerges as a separated pair of electron-dense shells. The viral envelope contains a lipid bilayer by which the membrane (M), envelope (E) and spike (S) structural proteins are harbored ( Figure 1 ) (12, 13) . The genome of CoVs is Monopartite, linear, single-stranded positive-sense RNA (+ssRNA) (~30 kb in size), Capped at the 5' end, and poly adenylated at the 3' end with at least six open reading frames (ORFs) and other subsidiary genes (14) . The RNA genome includes 29,891 nucleotides (Gene Bank accession number MN908947), encoding 9860 amino acids. The 5' terminal two-thirds of the genome contains two ORFs, ORF1 and ORF2 that encodes pp1a and pp1ab polyproteins, which is further split into 11 and 16 proteins, respectively, which encode non-structural proteins (nsps) (13, 15) . These proteins are processed into the viral polymerase (RdRp) and other non-structural proteins involved in RNA synthesis (16) . The structural proteins including spike (S), envelope (E), membrane (M), and nucleocapsid (N) are arranged in the order of one-third 3' terminal of the genome (15) . One of the most important genes that can help researchers to produce vaccine in the future is S gene because this gene product has an effective role in receptor binding and host specificity (17) . Recently reported that between the SARS-CoV genome sequence and the novel coronavirus exist 82% similarity, thus, named 2019-nCoV by WHO (18) . This theory may be indicating that 2019-nCoV uses the same SARS-CoV mechanism i.e. through angiotensin-converting enzyme2 (ACE2) receptor and the TMPRSS2 protease to infect the human cells. Coronavirus spike (S) protein facilitates virus entry into target cells. The binding of SARS to the receptor and its entry into the cell depends on a cellular protease (19) . Sequence analysis has shown that some of the 2019-nCoV clusters and bat-associated SARS76 CoV viruses (SARSr-CoV) can use the ACE2 receptor to enter the host cell. Analysis of the receptor-binding motif (RBM) and a part of the receptor-binding domain (RBD) that interacts with ACE2, revealed that most of the essential amino acid residues were retained at 2019-nCoV for ACE2 binding, but in the SARSr-CoV S proteins were not observed. It was found that it does not use ACE2 for entry into the cells and need priming the S protein for binding to ACE2 (20) . It has been reported that entry of SARS-CoV-2 to host cells may block via a clinical antagonist of the TMPRSS2, a cellular serine protease, that is recruited via SARS-CoV-2 to S protein priming. These new findings have significant implications for our knowledge about the transmission and pathogenesis of SARS-CoV-2 and treatment approaches (21) . Shieh W-J, et al., reported that SARS-CoV might goal a full spectrum of similar cells. The SARS-CoV in the respiratory system leads to infect mostly pneumocytes and macrophages (22) . In addition to lung, other tissues can expression of ACE2. Thus, SARS-CoV may extent to extrapulmonary organs. While the affinity of SARS-S and SARS-2-S to ACE2 receptor has been comparable, therefore we still expect this for SARS-CoV-2. Previous studies showed that in the upper airways a mild expression of ACE2 (23,24) may be able to reduce SARS-CoV spread, given that the high dispersion ability of SARS91 CoV-2 against SARS-CoV (25). Definitively, it is important to note that the high-level expression of ACE2 can prevent lung damage. However, its downregulated through SARS-S, which lead to stimulate SARS. To enter the virus into host cells and covers S protein cleavage at the S1/S2 and the S2′ sites, the need to specific proteases in the host cells for priming of coronavirus S proteins (26) . The cutting site of SARS-2-S, several arginine residues (multibasic) that shows high sensitivity for cutting. Actually, into the host cells, SARS-2-S was proficiently cleaved, fallowing by cleaved S protein was incorporated into vesicular stomatitis virus (VSV) particles. Notably, the area in which the incision has occurred can define the zoonotic potential of coronaviruses (27, 28) ; the SARS-CoV100 2 and coronavirus have the most closely associated. SARS-CoV can use endosomal cysteine protease to priming S-protein in TMPRSS2 negative cells. Nevertheless, priming of protein S via TMPRSS2 protease is required for virus entry into target cells, and the spread of the virus in infected host cells (29) . After the first reports of 2019-nCoV outbreak in Wuhan, Hubei, China, in December 2019, the virus quickly spread throughout China during several weeks, and then on the other Asian countries, the Middle East, Africa, the Americas, Oceania, and Europe. In accordance with the daily information of the WHO, the pandemic of 2019 nCoV till now caused 1,861,672 positive cases and 114,980 deaths in the worldwide by 13th April 2020 (30) , that lead to a main global health concern (Table 2) and 2019-nCoV infections can be hidden for 2-14 d without any symptoms generally, but can display from 3-7 d mostly (34) . After the incubation period of the disease, the presentations are mostly fever, exhaustion and cough, which are probably accompanied by nasal congestion, runny nose, expectoration, and rarely diarrhea and headache. Typically, fever can be low to moderate, and even with no fever (35) . After a week and with progress of displaying the disease, other sings such as dyspnea, cyanosis, and eventually systemic fatal symptoms appear, including malaise or restlessness, poor feeding, bad appetite, less activity, and respiratory failure. The late signs that could occur in severe cases may be accompanied by septic shock, metabolic acidosis, irreversible bleeding and coagulation dysfunction (34, 36) . The clinical presentations and reports from several investigations are summarized in Table 3 (33, (37) (38) (39) (40) (41) . The new virus is diffused through droplets of the respiratory system when patients with infection cough, sneeze, or even during the conversation. Furthermore, other ways for transmission of the virus are embracing and close contact (e.g., contact with the mouth, nose or eyes conjunctiva via polluted hands). It has been not recognized so far that spread can happen by mother to infant or breast feeding (34) . 2019-nCoV leads to an acute resolved infection, which could be lethal with a mortality rate of about 2%. In the case of severe infection, it might lead to expiration of the patients due to severe alveolar injury and advanced respiratory failure (42, 43) . However, post-mortem biopsy might be taken from the liver, heart, and lung tissues. In the lung histological studies, bilateral diffuse alveolar damage with cellular fibromyxoid exudate might be seen. Patent desquamation of the pneumocytes and hyaline membrane construction in the right lung has also been seen to demonstrate acute respiratory failure (44) . On the other hand, biopsy assay in the left lung exhibited pulmonary oedema with hyaline membrane construction. In the whole lung tissues, interstitial mononuclear inflammatory infiltrates occur mostly by lymphocytes. Furthermore, syncytial cells with abnormal puffy pneumocytes characterized via bulky nuclei, amphophilic granular cytoplasm, and noticeable nucleoli in the intra-alveolar spaces were recognized. These features display viral cytopathic-like variations (45) . Pneumonia patients with initial stage lung X-ray analysis demonstrate several small patchy shadows and interstitial variations significant in the lung periphery (6) . In patients with severe disease, more progress to bilateral multiple ground-glass opacity, infiltrating shadows, and pulmonary merging, with rare pleural effusion, can be seen. In both lungs of the youngsters with severe disease, multiple lobar lesions may be observed (46) . Moreover, biopsy of the liver indicated modest microvascular steatosis and slight lobular activity; nevertheless, there was no definite proof to support 2019-nCoV contamination or drug-induced liver damage as a result. Subsequently, biopsy observations showed that no clear histological variations were seen in the heart tissue, proposing that 2019-nCoV contamination might not directly damage the heart (47) . A radiograph of an infected person's chest is shown in Figure 2 , as an example. (Table 4 ). In addition, different companies are working hard for produce vaccine; experts estimate it could take between 12-18 months to develop a vaccine ready for market. Supplementary Table 1 recommended. Certain drugs such as methylprednisolone intravenously (1-2 mg/kg/d) are suggested for 3-5 d, but not for long-term consumption (47, (50) (51) (52) (53) . In severe patients, immunoglobulin can also be recommended intravenously. The suggested dose is 1.0 g/kg/d for 2 d, or 400 mg/kg/d for 5 d (51, 54, 55) . In patients with blood circulation problems, drugs that are vasoactive can be used for recovering microcirculation on the basis of sufficient liquid intake (47) . Cases who had acute renal damage should be given kidney tests function. In children, if intracranial hypertension and convulsion happens, there is a need to decrease the intracranial pressure and control convulsion to be suitable (54, 55) . There is speculation that patients with 2019-nCoV who are receiving ACE inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes (56, 57) . The ACE2 is a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and reninangiotensin aldosterone system inhibitors can increase the ACE2 levels (58) . Finally, in the patients who had respiratory complication despite nasal catheter or mask oxygenation, heated humidified high-flow nasal cannula (HHHFNC), non-invasive ventilation such as continuous positive airway pressure (CPAP), or non-invasive high-frequency ventilation can be used. If improvement is not possible, mechanical ventilation with endotracheal intubation and a protective lung ventilation strategy should be adopted (46) . 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