In humans, infections with the human coronavirus (HCoV) strains HCoV‑229E, HCoV‑OC43, HCoV‑NL63 and HCoV‑HKU1 usually result in mild, self‑limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12years owing to their ability to cause community and health‑care‑associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus‑based and host‑based therapeutic options for CoV infections Reference & source information :https://www.researchgate.net/ Read more on :

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19. In the present study, we focus on defining the host response to SARS-CoV-2 and other human respiratory viruses in cell lines, primary cell cultures, ferrets, and COVID-19 patients. In general, our data show that the overall transcriptional footprint of SARS-CoV-2 infection was distinct in comparison with other highly pathogenic coronaviruses and common respiratory viruses such as IAV, HPIV3, and RSV. It is noteworthy that, despite a reduced IFN-I and -III response to SARS-CoV-2, we observed a consistent chemokine signature. One exception to this observation is the response to high-MOI infection in A549-ACE2 and Calu-3 cells, where replication was robust and an IFN-I and -III signature could be observed. In both of these examples, cells were infected at a rate to theoretically deliver two functional virions per cell in addition to any defective interfering particles within the virus stock that were not accounted for by plaque assays. Under these conditions, the threshold for PAMP may be achieved prior to the ability of the virus to evade detection through production of a viral antagonist. Alternatively, addition of multiple genomes to a single cell may disrupt the stoichiometry of viral components, which, in turn, may itself generate PAMPs that would not form otherwise. These ideas are supported by the fact that, at a low-MOI infection in A549-ACE2 cells, high levels of replication could also be achieved, but in the absence of IFN-I and -III induction. Taken together, these data suggest that, at low MOIs, the virus is not a strong inducer of the IFN-I and -III system, as opposed to conditions where the MOI is high. These dynamics are also likely to contribute to development of COVID-19 during the course of infection (Wolfel et al., 2020). A recurrent observation in each of our systems is a robust production of cytokines and their subsequent transcriptional response. According to our longitudinal in vivo data, this response starts as early as 3 days after infection and continues beyond clearance of the virus. A recent study analyzing severe versus mild cases of COVID-19 showed that peripherally derived macrophages predominated in the lungs of severe cases (Liao et al., 2020). Consistent with this, we found, in all of our systems, significant induction of monocyte-associated chemokines such as CCL2 and CCL8. In addition, our data suggest that neutrophils could also contribute to the disease observed in COVID-19 patients, as demonstrated by CXCL2 and CXCL8 induction. This is consistent with data showing elevated circulating neutrophil levels among COVID-19 patients (Chen et al., 2020, Qin et al., 2020), which may have prognostic value for identifying individuals at risk for developing severe disease. It is also noteworthy that two of the cytokines uniquely elevated in response to SARS-CoV-2 are IL-6 and IL1RA, suggesting that there might be a parallel between COVID-19 and cytokine release syndrome (CRS), a complication commonly seen following CAR T-cell treatment (Giavridis et al., 2018). Should this be true, drugs such as tocilizumab and anakinra may prove to be beneficial for treatment of COVID-19 (Norelli et al., 2018). Future studies will be needed to address this formally. Like SARS-CoV-2, the clinical manifestation of SARS-CoV-1 has been proposed to stem from a dysregulated immune response in patients and delayed expression of IFN-I (Channappanavar et al., 2016, Law et al., 2005, Menachery et al., 2014). Based on animal models, SARS-CoV-1 has been found to induce a robust cytokine response that generally shows a delay in IFN-I, culminating in improper recruitment of inflammatory monocyte-macrophage populations (Channappanavar et al., 2016). This dynamic seems to be in line with what we observed with SARS-CoV-2 because low levels of IFN-I and -III are likely produced in response to infection. Given the moderate viral replication levels observed in vivo, one explanation for the low IFN expression could be that a small subset of cells is refractory to the antagonistic mechanism of SARS-CoV-2, producing sufficient amounts of IFN-I and/or IFN-III to guide immune cell activation and ISG induction. What makes SARS-CoV-2 distinct from other viruses used in this study is the propensity to selectively induce morbidity and mortality in older populations (Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, 2020). The physiological basis for this morbidity is believed to be selective death of type II pneumocytes, which results in loss of air exchange and fluid leakage into the lungs (Qian et al., 2013, Xu et al., 2020). Although it remains to be determined whether the inappropriate inflammatory response to SARS-CoV-2 is responsible for the abnormally high lethality in older populations, it does explain why the virus is generally asymptomatic in young people with healthy and robust immune systems (Lu et al., 2020). Given the results here, it is tempting to speculate that an already restricted immune response in the aging population prevents successful inhibition of viral spread at early stages of infection, further exacerbating the morbidity and mortality observed for this age group (Jing et al., 2009, Montecino-Rodriguez et al., 2013). Taken together, the data presented here suggest that the response to SARS-CoV-2 is imbalanced with regard to controlling virus replication versus activation of the adaptive immune response. Given this dynamic, treatments for COVID-19 have less to do with the IFN response and more to do with controlling inflammation. Because our data suggest that numerous chemokines and ILs are elevated in COVID-19 patients, future efforts should focus on U.S. Food and Drug Administration (FDA)-approved drugs that can be rapidly deployed and have immunomodulating properties. Reference & source information : https://www.sciencedirect.com/ Read More on:

Human monoclonal antibodies block the SARS-CoV-2 RBD protein-hACE2 protein interaction a ELISA binding assay of COVID-19 patient sera to ELISA plate coating of SARS-CoV-2 S1 protein. b ELISA binding assay of COVID-19 patient sera to ELISA plate coating of SARS-CoV-2 RBD protein. c COVID-19 patient serum-mediated inhibition of the SARS-CoV-2 S1 protein binding to hACE2 protein by ELISA. d An overall strategy of anti-SARS-CoV-2 RBD mAbs. e Flow cytometry analysis of SARS-CoV-2 RBD-specific IgG+ B cells in PBMCs of healthy donor and patient XFQ. f Specificity of mAbs (311mab–31B5, −32D4 and −31B9 clones) to SARS-CoV-2 RBD protein by ELISA. g ELISA analysis of SARS-CoV-2 RBD-hACE2 interaction inhibited by 311mab–31B5, −32D4, and −31B9 mAbs. h Flow cytometry analysis of SARS-CoV-2 RBD-hACE2 interaction inhibited by 311mab–31B5, −32D4, and −31B9 mAbs. The numbers adjacent to the outlined areas indicate the percentages of anti-mouse IgG+ hACE2-plasmid transiently transfected 293T cells, which are summarized in i (left panel). i (right panel) Mean fluorescence intensity (MFI) of Alexa Fluor 647 anti-mouse IgG in anti-mouse IgG+ hACE2-plasmid transiently transfected 293T cells. j Antibody-mediated blocking of luciferase-encoding SARS-Cov-2 typed pseudovirus into hACE2/293T cells. NC, negative control. HD, healthy donor. The data are representative of two independent experiments with three replicates per group (f, g, i, j; error bars in f, g, i, j indicate the SD) Next, we set out to clone human mAbs using the blood samples from three COVID-19 recovered patients, of which their sera showed potent hACE2 receptor binding inhibition. To this end, we sorted each SARS-CoV-2 RBD-specific, IgG class-switched memory B cell into a single well of the 96-well microplates. Subsequently, we used reverse transcription polymerase chain reaction to amplify IgG variable heavy chain (VH) and light chain (VL) from each single memory B cell. After cloning both VH and VL, we inserted both sequences into expression plasmids that encoding constant regions of human IgG1 heavy chain and light chain (Fig. 1d).21 We found that SARS-CoV-2 RBD-specific, IgG-positive memory B cells only enriched in COVID-19 recovered patients, but not in healthy controls (Fig. 1e), suggesting the specificity of our sorting strategy. After antibody cloning, we acquired three pairs of IgG VHs and VLs inserted expression plasmids. Finally, we expressed these paired plasmids encoding IgG VH and VL sequences and named these three mAbs as 311mab–31B5, 311mab–32D4 and 311mab–31B9, respectively. We first examined whether these human mAbs were able to bind to SARS-CoV-2 RBD protein by ELISA. The results showed that all three mAbs strongly and specifically bind to the RBD protein (Fig. 1f). Next, we tested whether these mAbs can block the interaction between SARS-CoV-2 RBD and hACE2. We found that both 311mab-31B5 and 311mab-32D4 could efficiently block SARS-CoV-2 RBD-hACE2 interaction (IC50 = 0.0332, and 0.0450 μg/ml, respectively), while 311mab–31B9 clone failed to inhibit such an interaction (Fig. 1g). The 31B5- and 32D4-mediated inhibition of RBD-hACE2 interaction was also evidenced by flow cytometry analysis (Fig. 1h, i). Furthermore, we determined the neutralization of these three mAbs using a SARS-CoV-2 S pseudotyped lentiviral particle.22 In line with ELISA- and flow cytometry-based blockade results, both 311mab-31B5 and 311mab-32D4 effectively neutralized pseudovirus entry to host cells ectopically expressing hACE2 (IC50 = 0.0338, and 0.0698 μg/ml, respectively). As expected, 311mab-31B9 clone failed to show any neutralization activities (Fig. 1j). In conclusion, we have successfully cloned two human blocking mAbs using SARS-CoV-2 RBD-specific memory B cells isolated from recovered COVID-19 patients. These two mAbs can specifically bind to SARS-CoV-2 RBD, block the interaction between SARS-CoV-2 RBD and hACE2 receptor, and lead to efficient neutralization of SARS-CoV-2 S protein pseudotyped virus infection. Such human anti-SARS-CoV-2 RBD-hACE2 blocking mAbs are first reported, and hold great promise to be exploited as specific prophylactic and therapeutic agents against ongoing SARS-CoV-2 pandemic. Reference & Source Information: https://www.nature.com/ Read More on :

What is convalescent plasma? How could it help people with COVID-19? When people recover from COVID-19, their blood contains antibodies that their bodies produced to fight the coronavirus and help them get well. Antibodies are found in plasma, a component of blood. Convalescent plasma — literally plasma from recovered patients — has been used for more than 100 years to treat a variety of illnesses from measles to polio, chickenpox, and SARS. In the current situation, antibody-containing plasma from a recovered patient is given by transfusion to a patient who is suffering from COVID-19. The donor antibodies help the patient fight the illness, possibly shortening the length or reducing the severity of the disease. Though convalescent plasma has been used for many years, and with varying success, not much is known about how effective it is for treating COVID-19. There have been reports of success from China, but no randomized, controlled studies (the gold standard for research studies) have been done. Experts also don't yet know the best time during the course of the illness to give plasma. On March 24th, the FDA began allowing convalescent plasma to be used in patients with serious or immediately life-threatening COVID-19 infections. This treatment is still considered experimental. Who can donate plasma for COVID-19? In order to donate plasma, a person must meet several criteria. They have to have tested positive for COVID-19, recovered, have no symptoms for 14 days, currently test negative for COVID-19, and have high enough antibody levels in their plasma. A donor and patient must also have compatible blood types. Once plasma is donated, it is screened for other infectious diseases, such as HIV. Each donor produces enough plasma to treat one to three patients. Donating plasma should not weaken the donor's immune system nor make the donor more susceptible to getting reinfected with the virus. Is there an antiviral treatment for COVID-19? Currently there is no specific antiviral treatment for COVID-19. However, drugs previously developed to treat other viral infections are being tested to see if they might also be effective against the virus that causes COVID-19. Why is it so difficult to develop treatments for viral illnesses? An antiviral drug must be able to target the specific part of a virus's life cycle that is necessary for it to reproduce. In addition, an antiviral drug must be able to kill a virus without killing the human cell it occupies. And viruses are highly adaptive. Because they reproduce so rapidly, they have plenty of opportunity to mutate (change their genetic information) with each new generation, potentially developing resistance to whatever drugs or vaccines we develop. What treatments are available to treat coronavirus? Currently there is no specific antiviral treatment for COVID-19. However, similar to treatment of any viral infection, these measures can help: While you don't need to stay in bed, you should get plenty of rest. Stay well hydrated. To reduce fever and ease aches and pains, take acetaminophen. Be sure to follow directions. If you are taking any combination cold or flu medicine, keep track of all the ingredients and the doses. For acetaminophen, the total daily dose from all products should not exceed 3,000 milligrams. Is it safe to take ibuprofen to treat symptoms of COVID-19? Some French doctors advise against using ibuprofen (Motrin, Advil, many generic versions) for COVID-19 symptoms based on reports of otherwise healthy people with confirmed COVID-19 who were taking an NSAID for symptom relief and developed a severe illness, especially pneumonia. These are only observations and not based on scientific studies. The WHO initially recommended using acetaminophen instead of ibuprofen to help reduce fever and aches and pains related to this coronavirus infection, but now states that either acetaminophen or ibuprofen can be used. Rapid changes in recommendations create uncertainty. Since some doctors remain concerned about NSAIDs, it still seems prudent to choose acetaminophen first, with a total dose not exceeding 3,000 milligrams per day. However, if you suspect or know you have COVID-19 and cannot take acetaminophen, or have taken the maximum dose and still need symptom relief, taking over-the-counter ibuprofen does not need to be specifically avoided. Are chloroquine/hydroxychloroquine and azithromycin safe and effective for treating COVID-19? Early reports from China and France suggested that patients with severe symptoms of COVID-19 improved more quickly when given chloroquine or hydroxychloroquine. Some doctors were using a combination of hydroxychloroquine and azithromycin with some positive effects. Hydroxychloroquine and chloroquine are primarily used to treat malaria and several inflammatory diseases, including lupus and rheumatoid arthritis. Azithromycin is a commonly prescribed antibiotic for strep throat and bacterial pneumonia. Both drugs are inexpensive and readily available. Hydroxychloroquine and chloroquine have been shown to kill the COVID-19 virus in the laboratory dish. The drugs appear to work through two mechanisms. First, they make it harder for the virus to attach itself to the cell, inhibiting the virus from entering the cell and multiplying within it. Second, if the virus does manage to get inside the cell, the drugs kill it before it can multiply. Azithromycin is never used for viral infections. However, this antibiotic does have some anti-inflammatory action. There has been speculation, though never proven, that azithromycin may help to dampen an overactive immune response to the COVID-19 infection. However, the most recent human studies suggest no benefit — and possibly a higher risk of death due to lethal heart rhythm abnormalities — with both hydroxychloroquine and azithromycin used alone. The drugs are especially dangerous when used in combination. Based on these new reports, the FDA now formally recommends against taking chloroquine or hydroxychloroquine for COVID-19 infection unless it is being prescribed in the hospital or as part of a clinical trial. Three days earlier a National Institutes of Health (NIH) panel released a similar strong statement advising against the use of the combination of hydroxychloroquine and azithromycin. Is the antiviral drug remdesivir effective for treating COVID-19? Scientists all over the world are testing whether drugs previously developed to treat other viral infections might also be effective against the new coronavirus that causes COVID-19. One drug that has received a lot of attention is the antiviral drug remdesivir. That's because the coronavirus that causes COVID-19 is similar to the coronaviruses that caused the diseases SARS and MERS — and evidence from laboratory and animal studies suggests that remdesivir may help limit the reproduction and spread of these viruses in the body. In particular, there is a critical part of all three viruses that can be targeted by drugs. That critical part, which makes an important enzyme that the virus needs to reproduce, is virtually identical in all three coronaviruses; drugs like remdesivir that successfully hit that target in the viruses that cause SARS and MERS are likely to work against the COVID-19 virus. Remdesivir was developed to treat several other severe viral diseases, including the disease caused by Ebola virus (not a coronavirus). It works by inhibiting the ability of the coronavirus to reproduce and make copies of itself: if it can't reproduce, it can't make copies that spread and infect other cells and other parts of the body. Remdesivir inhibited the ability of the coronaviruses that cause SARS and MERS to infect cells in a laboratory dish. The drug also was effective in treating these coronaviruses in animals: there was a reduction in the amount of virus in the body, and also an improvement in lung disease caused by the virus. The drug appears to be effective in the laboratory dish, in protecting cells against infection by the COVID virus (as is true of the SARS and MERS coronaviruses), but more studies are underway to confirm that this is true. Remdesivir was used in the first case of COVID-19 that occurred in Washington state, in January 2020. The patient was severely ill, but survived. Of course, experience in one patient does not prove the drug is effective. Two large randomized clinical trials are underway in China. The two trials will enroll over 700 patients, and are likely to definitively answer the question of whether the drug is effective in treating COVID-19. The results of those studies are expected in April or May 2020. Studies also are underway in the United States, including at several Harvard-affiliated hospitals. It is hard to predict when the drug could be approved for use and produced in large amounts, assuming the clinical trials indicate that it is effective and safe. I've heard that high-dose vitamin C is being used to treat patients with COVID-19. Does it work? And should I take vitamin C to prevent infection with the COVID-19 virus? Some critically ill patients with COVID-19 have been treated with high doses of intravenous (IV) vitamin C in the hope that it will hasten recovery. However, there is no clear or convincing scientific evidence that it works for COVID-19 infections, and it is not a standard part of treatment for this new infection. A study is underway in China to determine if this treatment is useful for patients with severe COVID-19; results are expected in the fall. The idea that high-dose IV vitamin C might help in overwhelming infections is not new. A 2017 study found that high-dose IV vitamin C treatment (along with thiamine and corticosteroids) appeared to prevent deaths among people with sepsis, a form of overwhelming infection causing dangerously low blood pressure and organ failure. Another study published last year assessed the effect of high-dose vitamin C infusions among patients with severe infections who had sepsis and acute respiratory distress syndrome (ARDS), in which the lungs fill with fluid. While the study's main measures of improvement did not improve within the first four days of vitamin C therapy, there was a lower death rate at 28 days among treated patients. Though neither of these studies looked at vitamin C use in patients with COVID-19, the vitamin therapy was specifically given for sepsis and ARDS, and these are the most common conditions leading to intensive care unit admission, ventilator support, or death among those with severe COVID-19 infections. Regarding prevention, there is no evidence that taking vitamin C will help prevent infection with the coronavirus that causes COVID-19. While standard doses of vitamin C are generally harmless, high doses can cause a number of side effects, including nausea, cramps, and an increased risk of kidney stones. What is serologic (antibody) testing for COVID-19? What can it be used for? A serologic test is a blood test that looks for antibodies created by your immune system. There are many reasons you might make antibodies, the most important of which is to help fight infections. The serologic test for COVID-19 specifically looks for antibodies against the COVID-19 virus. Your body takes at least five to 10 days after you have acquired the infection to develop antibodies to this virus. For this reason, serologic tests are not sensitive enough to accurately diagnose an active COVID-19 infection, even in people with symptoms. However, serologic tests can help identify anyone who has recovered from coronavirus. This may include people who were not initially identified as having COVID-19 because they had no symptoms, had mild symptoms, chose not to get tested, had a false-negative test, or could not get tested for any reason. Serologic tests will provide a more accurate picture of how many people have been infected with, and recovered from, coronavirus, as well as the true fatality rate. Serologic tests may also provide information about whether people become immune to coronavirus once they've recovered and, if so, how long that immunity lasts. In time, these tests may be used to determine who can safely go back out into the community. Scientists can also study coronavirus antibodies to learn which parts of the coronavirus the immune system responds to, in turn giving them clues about which part of the virus to target in vaccines they are developing. Serological tests are starting to become available and are being developed by many private companies worldwide. However, the accuracy of these tests needs to be validated before widespread use in the US. Reference & Source information: https://www.health.harvard.edu/ Read More on: https://www.health.harvard.edu/diseases-and-conditions/treatments-for-covid-19

we attempted to evaluate the changes in levels of some air pollutants (mainly PM10, NO2and SO2) in Salé city (North-Western Morocco) during the lockdown measures. In this context, a continuous measurement of PM10, SO2and NO2was carried before and during the Covid-19 lockdown period. As a consequence of the security measures and control actions undertaken, the emissions from vehicle exhaust and industrial production were significantly reduced, which contribute to the decrease in the concentrations of the studied pollutants. The obtained results showed that the difference between the concentrations recorded before and during the lockdown period were respectively 75%, 49% and 96% for PM10, SO2and NO2. PM10levels were much less reduced than NO2. The three-dimensional air mass backward trajectories, using the HYSPLIT model, demonstrated the benefits of PM10local emission reductions related to the lockdown were overwhelmed by the contribution of long-range transported aerosols outside areas. In addition, noteworthy differences in the air mass back trajectories and the meteorology between these two periods were evidenced. Conclusion The reduction in PM10, SO2 and NO2 concentrations, in the studied area, can mainly be attributed to the drastic measures limiting human movement and industrial activities during the Covid-19 pandemic, which resulted in a significant reduction in emissions from vehicle exhaust and industrial production. The authors believe that the PM10, NO2 and SO2 concentrations will continue to decrease and keep down to minimal levels during the Covid-19 lockdown period. Reference & source information : https://www.journals.elsevier.com/ Read More on :

The life cycle of SARS-CoV-2 Credit and Source of Information: rna-seqblog.com A high resolution gene map reveals many viral RNAs with unknown functions and modifications Jean and Peter Medawar wrote in 1977 that a virus is “simply a piece of bad news wrapped up in proteins.” The “bad news” in the SARS-CoV-2 case is the new coronavirus carries its mysterious genome in the form of a very long ribonucleic acid (RNA) molecule. Grappling with COVID-19 pandemic, the world seems to be lost with no sense of direction in uncovering what this coronavirus (SARS-Cov-2) is composed of. Being an RNA virus, SARS-Cov-2 enters host cells and replicates a genomic RNA and produce many smaller RNAs (called “subgenomic RNAs”). These subgenomic RNAs are used for the synthesis of various proteins (spikes, envelopes, etc.) that are required for the beginning of SARS-Cov-2 lineage. Thus, the smaller RNAs make good targets for messing up new coronavirus’s conquering of our immune system. Though recent studies reported the sequence of the RNA genome, they only predicted where their genes might be, leaving the world still drown in disorientation. When the spike protein of SARS-CoV-2 binds to the receptor of the host cell, the virus enters the cell, and then the envelope is peeled off, which let genomic RNA be present in the cytoplasm. The ORF1a and ORF1b RNAs are made by genomic RNA, and then translated into pp1a and pp1ab proteins, respectively. Protein pp1a and ppa1b are cleaved by protease to make a total of 16 nonstructural proteins. Some nonstructural proteins form a replication/transcription complex (RNA-dependent RNA polymerase, RdRp), which use the (+) strand genomic RNA as a template. The (+) strand genomic RNA produced through the replication process becomes the genome of the new virus particle. Subgenomic RNAs produced through the transcription are translated into structural proteins (S: spike protein, E: envelope protein, M: membrane protein, and N: nucleocapsid protein) which form a viral particle. Spike, envelope and membrane proteins enter the endoplasmic reticulum, and the nucleocapsid protein is combined with the (+) strand genomic RNA to become a nucleoprotein complex. They merge into the complete virus particle in the endoplasmic reticulum-Golgi apparatus compartment, and are excreted to extracellular region through the Golgi apparatus and the vesicle. Led by Professors KIM V. Narry and CHANG Hyeshik, the research team of the Center for RNA Research within the Institute for Basic Science (IBS), South Korea, succeeded in dissecting the architecture of SARS-CoV-2 RNA genome, in collaboration with Korea National Institute of Health (KNIH) within Korea Centers for Disease Control & Prevention (KCDC). The researchers experimentally confirmed the predicted subgenomic RNAs that are in turn translated into viral proteins. Furthermore, they analyzed the sequence information of each RNA and revealed where genes are exactly located on a genomic RNA. “Not only to detailing the structure of SARS-CoV-2, we also discovered numerous new RNAs and multiple unknown chemical modification on the viral RNAs. Our work provides a high-resolution map of SARS-CoV-2. This map will help understand how the virus replicates and how it escapes the human defense system,” explains Professor KIM V. Narry, the corresponding author of the study. Composition of genomic and subgenomic RNAs of SARS-CoV-2 and schematic diagram of virus particle structure SARS-CoV-2 RNAs are known to consists of ORF1a, ORF1b, ORFS, ORFE, ORFM, ORFN, ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10. This study, all RNAs except ORF10 were experimentally validated. The prediction that ORF10 exists seems to be wrong. There are nine subgenomic RNAs (S, E, M, N, 3a, 6, 7a, 7b, 8) indeed transcribed from genomic RNAs. Among them, S, E, M, and N RNAs are translated into each protein, respectively, forming a structure of virus particle (S: spike protein, E: envelope protein, M: membrane protein, and N: nucleocapsid protein). It was previously known that 10 subgenomic RNAs make up the viral particle structure. However, the research team confirmed that 9 subgenomic RNAs actually exist, invalidating the remaining one subgenomic RNA. Researchers also found that there are dozens of unknown subgenomic RNAs, owing to RNA fusion and deletion events. “Though it requires further investigation, these molecular events may lead to the relatively rapid evolution of coronavirus. Moreover, we find multiple unknown chemical modifications on the viral RNAs. It is unclear yet what these modifications do, but a possibility is that they may assist the virus to avoid the attack from the host,” says Prof. Kim. The research team suggests that modified RNAs may have new properties that are different from unmodified RNAs even though they have the same genetic information in terms of RNA base sequence. They believe if they figure out the unknown characteristics of RNA, the findings may offer a new clue for combatting the new coronavirus. Newly discovered chemical modification will also help to understand the life cycle of the virus. SARS-CoV-2 genomic (gRNA) and subgenomic RNAs (S, 3a, E, M, 6, 7a, 7b, 8, and N) and the location of RNA modifications 📷 Modification levels are different between RNA transcripts, and the most frequent modification site is designated by red arrowhead. Behind the success of the study is the research team’s pairing of two complementary sequencing techniques; DNA nanoball sequencing and nanopore direct RNA sequencing. The nanopore direct RNA sequencing allows to directly analyze the entire long viral RNA without fragmentation. Conventional RNA sequencing methods usually require a step-by-step process of cutting and converting RNA to DNA before reading RNA. Meanwhile, the DNA nanoball sequencing can read only short fragments, but has the advantage of analyzing a large number of sequences with high accuracy. These two techniques turned out to be highly complementary to each other to analyze the viral RNAs. “Now we have secured a high resolution gene map of the new coronavirus that guides us where to find each bit of genes on all of the total SARS-CoV-2 RNAs (transcriptome) and all modifications RNAs (epitranscriptome). It is time to explore the functions of the newly discovered genes and the mechanism underlying viral gene fusion. We also have to work on the RNA modifications to see if they play a role in virus replication and immune response. We firmly believe that our study will contribute to the development of diagnostics and therapeutics to combat the virus more effectively,” notes Professor KIM V. Narry. Source – Institute for Basic Science (IBS), Korea Kim D, Lee JY, Yang JS, Kim JW, Kim VN, Chang H. (2020) The architecture of SARS-CoV-2 transcriptome. Cell [Epub ahead of print]. Ref and Source of information : https://www.rna-seqblog.com/the-architecture-of-sars-cov-2-transcriptome/

Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited. This highlights the importance of advancing our knowledge on the replication of these viruses and their interactions with the host. Compared to other +RNA viruses, coronaviruses have an exceptionally large genome and employ a complex genome expression strategy. Next to a role in basic virus replication or virus assembly, many of the coronavirus proteins expressed in the infected cell contribute to the coronavirus-host interplay. For example, by interacting with the host cell to create an optimal environment for coronavirus replication, by altering host gene expression or by counteracting the host’s antiviral defenses. These coronavirus–host interactions are key to viral pathogenesis and will ultimately determine the outcome of infection. Due to the complexity of the coronavirus proteome and replication cycle, our knowledge of host factors involved in coronavirus replication is still in an early stage compared to what is known for some other +RNA viruses. This review summarizes our current understanding of coronavirus–host interactions at the level of the infected cell, with special attention for the assembly and function of the viral RNA-synthesising machinery and the evasion of cellular innate immune responses. Concluding Remarks Insight into coronavirus-host interactions, obtained, e.g., using systematic screening approaches, does not only yield valuable information on the molecular details of the replicative cycle and pathogenesis, but can also be a starting point for the development of antiviral strategies. Virus binding and entry are the first steps of the replication cycle that can be targeted with inhibitors. Several well-known inhibitors of endosomal acidification, like ammonium chloride and the FDA-approved anti-malaria drug chloroquine, have been shown to block entry of coronaviruses (Takano et al. 2013; Keyaerts et al. 2009; Krzystyniak and Dupuy 1984; Payne et al. 1990; Kono et al. 2008), including SARS-CoV and MERS-CoV (Keyaerts et al. 2004; de Wilde et al. 2014). In addition, peptides have been developed that block fusion by interfering with the interaction between the HR1 and HR2 domains of the S protein, preventing the formation of a fusogenic complex or blocking S protein oligomerisation [reviewed in (Du et al. 2009)]. Interferon (IFN) was shown to trigger the innate immune response in coronavirus-infected cells, leading to transcription of many ISGs that have a role in controlling infection (Schoggins and Rice 2011). Treatment with type-I IFNs inhibits coronavirus replication in cell culture (Garlinghouse et al. 1984; Taguchi and Siddell 1985; Haagmans et al. 2004; Paragas et al. 2005; Zheng et al. 2004; de Wilde et al. 2013b) and, for example, protected type-I pneumocytes against SARS-CoV infection in macaques (Haagmans et al. 2004). Despite the potency of IFN as an antiviral agent, its side effects like fatigue, malaise, apathy, and cognitive changes (Dusheiko 1997) emphasize the need for developing IFN-free therapeutic strategies. Besides inhibitors directed at viral enzymes (Kim et al. 2016), such therapeutic strategies could also involve host-directed approaches, based on the knowledge obtained on coronavirus–host interactions. The host-directed approach might lower the chance of development of antiviral resistance and could yield a broad-spectrum therapeutic strategy to treat infections with currently problematic coronaviruses and new variants that will undoubtedly emerge in the future Reference & source Information : https://link.springer.com/ Read More on:

Chloroquine approved for emergency use by US FDA The US Food and Drug Administration (FDA) approved limited emergency use for chloroquine and hydroxychloroquine as a treatment for COVID-19. Favilavir, the first approved coronavirus drug in China The National Medical Products Administration of China has approved the use of Favilavir, an anti-viral drug, as a treatment for coronavirus. The drug has reportedly shown efficacy in treating the disease with minimal side effects in a clinical trial involving 70 patients Pharmaceutical companies involved in developing coronavirus drugs/vaccines Fusogenix DNA vaccine by Entos Pharmaceuticals ChAdOx1 nCoV-19 by University of Oxford Gimsilumab by Roivant Sciences AdCOVID by Altimmune Coronavirus vaccine by Medicago AT-100 by Airway Therapeutics TZLS-501 by Tiziana Life Sciences OYA1 by OyaGen BPI-002 by BeyondSpring Altimmune’s intranasal coronavirus vaccine INO-4800 by Inovio Pharmaceuticals and Beijing Advaccine Biotechnology NP-120 (Ifenprodil) by Algernon Pharmaceuticals APN01 by University of British Columbia and APEIRON Biologics mRNA-1273 vaccine by Moderna and Vaccine Research Center Avian Coronavirus Infectious Bronchitis Virus (IBV) vaccine by MIGAL Research Institute TNX-1800 by Tonix Pharmaceuticals Brilacidin by Innovation Pharmaceuticals Recombinant subunit vaccine by Clover Biopharmaceuticals Vaxart’s coronavirus vaccine CytoDyn-leronlimab Linear DNA Vaccine by Applied DNA Sciences and Takis Biotech BXT-25 by BIOXYTRAN to treat late-stage acute respiratory distress syndrome (ARDS) MERS CoV vaccines for coronavirus Novavax’s MERS coronavirus vaccine candidate Inovio Pharma’s INO-4700 Coronavirus drugs Remdesivir (GS-5734) by Gilead Sciences Actemra by Roche to treat coronavirus-related complications Biocryst Pharma’s Galidesivir, a potential antiviral  for coronavirus treatment Regeneron’s REGN3048-3051 and Kevzara SNG001 by Synairgen Research AmnioBoost by Lattice Biologics Other companies developing coronavirus vaccines/drugs Enanta Pharmaceuticals,Predictive Oncology,Emergent BioSolutions,Integral Molecular,CEL-SCI,AJ Vaccines,Takeda Pharmaceutical Company,Heat Biologics,Pfizer,Mateon Therapeutics,Hong Kong University of Science and Technology,Vaccine by Generex,Coronavirus drugs by Columbia University,Vaccine by Tulane University,Coronavirus vaccine by ImmunoPrecise Antibodies,Serum Institute of India,Southwest Research Institute,Zydus Cadila,NanoViricides,Vir Biotechnology,HIV drugs for coronavirus treatment. Reference & source information: https://www.clinicaltrialsarena.com/ Read More on: https://www.clinicaltrialsarena.com/analysis/coronavirus-mers-cov-drugs/

Bats have been implicated as the likely source of SARS-CoV-2, as both SARS-CoV and MERS-CoV are genetically similar to viruses recovered from bats, and bat coronaviruses can use human receptors for cell entry.However, phylogenetic studies, looking at sequence-based virus evolution, suggest that the virus is not transmitted directly from bats to humans but rather first infects intermediate animal hosts in close contact with humans. In the case of SARS-CoV, these can be civets or raccoon dogs sold at crowded markets; for MERS-CoV, they can be domesticated dromedary camels. Transmission from bats to intermediate hosts and then to humans, as well as from human to human, all involve viral adaptation, slight changes in viral sequence to improve fitness in the new host. This is not unique to coronaviruses, as endemics and pandemics also occur when novel influenza A virus strains emerge in the human population from an animal host.Similar to introduction of Ebolavirus and human immunodeficiency virus 1 by mammals, many other viruses circulating in wild animals have the potential for zoonotic transmission. SARS-CoV-2, the causative agent for the pandemic corona virus disease of 2019 (COVID-19) outbreak, was first found in Wuhan, China, and initial analysis of viral RNA obtained from patients hospitalized in late 2019 revealed it was 96% identical at the whole-genome level to a bat SARS-like coronavirus.7 Uniquely, SARS-CoV-2 can be transmitted by people who are infected but have no symptoms, not just by symptomatic patients. Concern about potential spread of SARS-CoV-2 to household cats has emerged from a news report of infection in a tiger in the Bronx Zoo. Ferrets can be infected, with intraspecies transmission,8 and cats can also be infected and transmit the virus to other cats, while dogs have low susceptibility. However, it is unknown if any of these animals can transmit the virus to humans. Reference & source information: https://www.ccjm.org/ Read More on :