Insight into 2019 novel coronavirus — an updated intrim review and lessons from SARS-CoV and MERS-CoV
The rapid spread of the coronavirus disease 2019 (COVID-19), caused by a zoonotic beta-coronavirus entitled 2019 novel coronavirus (2019-nCoV), has become a global threat. Awareness of the biological features of 2019-nCoV should be updated in time and needs to be comprehensively summarized to help optimize control measures and make therapeutic decisions.
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In late December 2019, a pneumonia outbreak of unknown etiology took place in Wuhan, Hubei province, China, and spread quickly nationwide. Chinese Center for Disease Control and Prevention (CCDC) identified a novel beta-coronavirus called 2019-nCoV, now officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ( ), that responsible for the pandemic. This was the third zoonotic coronavirus breakout in the first two decades of 21 st century that allowing human-to-human transmission and raising global health concerns. Chinese government had taken immediate, transparent and extraordinary measures, and reached initial achievements to control the outbreak. As of 11 March 2020, the pandemic caused accumulated 80955 confirmed cases and 3162 deaths in China, 37364 confirmed cases and 1130 deaths in 113 other countries worldwide. World Health Organization (WHO) deeply concerned the unprecedented swift global spread and severity of the outbreak, and by ignorance and inaction of some countries. Therefore, WHO announced the COVID-19 can be characterized as a pandemic
Biological features of 2019-nCoV and experiences combating COVID-19 should be updated in time and needs to be comprehensively summarized to help optimize control measures and make therapeutic decisions. What’s more, the 2019-nCoV demonstrated partial resemblance with SARS-CoV and MERS-CoV, in phylogenetic analysis, clinical manifestations and pathological findings. Scientific advances from the SARS and MERS outbreaks can provide valuable insight into rapid understanding and control measures of the current pandemic. We searched literatures and guidelines in Pubmed, Web of Science, Embase, CNKI, Wanfang, VIP, preprint bioRxiv and medRxiv databases from the earliest available date to 11 March, 2020. Initial search terms were "2019-nCoV" OR “2019 novel coronavirus" OR "SARS-CoV-2" OR "COVID-19" OR "corona virus disease 2019" OR "NCP" OR "Novel coronavirus pneumonia". Further search words were above keywords, "SARS" OR "SARS-CoV" OR "severe acute respiratory syndrome", "MERS" OR "MERS-CoV" OR "middle east respiratory syndrome", in combinations of with "spike protein" OR "genome" OR "reproductive number" OR "incubation period" OR "serial interval" OR "fatality rate" OR "clinical characteristics" OR "pathology" OR "autopsy" OR "treatment". Moreover, official documents and news released by National Health Commission of P.R. China, CCDC, CDC(USA) and WHO were accessed for up-to-date information on COVID-19. Only the articles in English or Chinese were considered.
In this review, we highlight the pandemic potential and pathological indications of emerging coronavirus, comprehensively and systematically summarize the up-to-date knowledge of the biological characteristics of 2019-nCoV, including virology and origin, epidemiology, clinical manifestations, pathology and treatment. Because of its natural structures and biological features to bind receptors on host cells, the spike protein of 2019-nCoV may played an essential role in disease spreading. We summarized all of the four available pathology studies of COVID-19 biopsy and autopsy, and compared the results with previous two deadly coronavirus diseases. New therapeutic measures are emerging one after another. Potential effective treatments were remdesivir, chloroquine, tocilizumab, convalescent plasma and vaccine immunization (when possible). Evidence-based medicine should always be advocated to guide our clinical decision.
Virology and origin
Coronavirus belongs to the subfamily Orthocoronavirinae in the family of Coronaviridae in the order Nidovirales, which mainly caused infections in respiratory and gastrointestinal tract. The 2019-nCoV is a novel enveloped beta-coronavirus which has a single stranded positive sense RNA genome
Concerning the origin of the virus, several phylogenetic analysis suggested the bat to be the most probable animal reservoir. Based on genome sequencing, 2019-nCoV is about 89% identical to bat SARS-like-CoVZXC21, 82% identical to human SARS-CoV and about 50% to MERS-CoV( ). As both SARS-CoV and MERS-CoV were transmitted from bats to palm civets or dromedary camels, and finally to humans, there should be another animal representing as an intermediate host between bat and human. Pangolins were suggested as the possible intermediate hosts, because their genome had approximately 85.5%-92.4% similarity to 2019-nCoV, representing two sub-lineages of 2019-nCoV in the phylogenetic tree, one of which (GD/P1L and GDP2S) was extremely closely related to 2019-nCoV( ). Other research suggested 2019-nCoV was the recombinant virus of bat coronavirus and snake coronavirus, by comparison in conjunction with relative synonymous codon usage bias among different animal species
Concerning the origin of the virus, several phylogenetic analysis suggested the bat to be the most probable animal reservoir. Based on genome sequencing, 2019-nCoV is about 89% identical to bat SARS-like-CoVZXC21, 82% identical to human SARS-CoV and about 50% to MERS-CoV( ). As both SARS-CoV and MERS-CoV were transmitted from bats to palm civets or dromedary camels, and finally to humans, there should be another animal representing as an intermediate host between bat and human. Pangolins were suggested as the possible intermediate hosts, because their genome had approximately 85.5%-92.4% similarity to 2019-nCoV, representing two sub-lineages of 2019-nCoV in the phylogenetic tree, one of which (GD/P1L and GDP2S) was extremely closely related to 2019-nCoV( ). Other research suggested 2019-nCoV was the recombinant virus of bat coronavirus and snake coronavirus, by comparison in conjunction with relative synonymous codon usage bias among different animal species
The truth is yet to be discovered.
The spike surface glycoprotein of coronavirus plays an essential role in binding to receptors on host cells and determines host tropism. Spike protein(S-protein) of 2019-nCoV is reported to bind with angiotensin-converting enzyme 2 (ACE2), the same receptor of SARS-CoV to invade host cells; whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4) as the primary receptor(
). The amino acid sequence of S-protein in 2019-nCoV is 76.47% identical to that of SARS-CoV, with the same structural confirmation and electrostatic properties in the interaction interface. The residues at positions 442, 472, 479, 487, and 491 in S-protein are reported to be at receptor complex interface with ACE2. However, four of the five critical residues in the 2019-nCoV S-protein are not preserved except for Tyr491. The binding free energy for 2019-nCoV S-protein to bind with human ACE2, increases by 28 kcal mol –1 compared to SARS-CoV S-protein (-50.6 kcal mol –1 vs. -78.6 kcal mol –1 ), due to the loss of hydrogen bond interactions by replacing Arg426 with Asn426( ). Furin-like cleavage site was supposed to be cleaved by proprotein convertase furin at special viral envelope glycoproteins, thereby enhancing viral fusion with host cell membranes. reported a furin-like cleavage site in the S-protein of 2019-nCoV, which is absent in other lineage b beta-coronaviruses. Another research team also discovered an “RRAR” furin recognition site by an insertion in the S1/S2 protease cleavage site in 2019-nCoV, instead of a single arginine in SARS-CoV. After quantifying the kinetics mediating the interaction via surface plasmon resonance, ACE2 is calculated to bind to 2019-nCoV ectodomain with ∼15 nM affinity, which is approximately 10- to 20-fold higher affinity than ACE2 binding to SARS-CoV( ). In all, the binding affinity between 2019-nCoV S-protein and ACE2 is comparable or even stronger than SARS-CoV S-protein and ACE2. This may explain the rapid development and strong ability of human-to-human transmission in COVID-19.
Pathology
Autopsy or biopsy studies would always be the key to understand the biological features of 2019-nCoV. Histological examinations of two patients underwent lung lobectomies for adenocarcinoma, revealed edema, proteinaceous exudate, focal hyperplasia of pneumocytes with only patchy inflammatory cellular infiltration without prominent hyaline membranes. Since both patients didn’t develop symptoms of COVID-19 pneumonia at the time of surgery, these changes likely represent an early phase of the lung pathology of COVID-19 pneumonia.
first reported the pathological characteristics of a patient who died from COVID-19. General observation from raw eyes showed less fibrosis and consolidation, instead more exudative lesions in COVID-19 than SARS. Microscopic examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates, indicating ARDS. Interstitial mononuclear inflammatory infiltrates were dominated by lymphocytes. Multinucleated syncytial cells with atypical enlarged pneumocytes showed viral cytopathic-like changes, without obvious intranuclear or intracytoplasmic viral inclusions. Results from flow cytometric analysis demonstrated that the counts of peripheral CD4+ and CD8 + T cells were substantially reduced, while their status were hyper-activated. It indicated the severe immune injury in later stage of COVID-19, but not by virus direct destruction( ). Based on the public database and single-cell RNA-Seq technique, pathological studies revealed that male donors had a higher ACE2-expressing cell ratio than their female counterparts. The only Asian male specimen has five more times as much as ACE2 expressing on the white and African American donors. This might explain why the 2019-nCov and previous SARS-CoV pandemic were concentrated in the Asian population and a heightened susceptibility of male patients, although more evidence was needed to draw such conclusion
Pathological manifestations of SARS and MERS infected patients may shed lights to control current 2019-nCoV pandemic. Histology examination demonstrated a considerably higher viral load of SARS-CoV RNA in lung and small bowels than other organs of the body, suggesting an reason for manifestation of pneumonia and diarrhea in SARS patients. Living 2019-nCoV was also detected positive in stool specimens and rectal swabs of infected patients, indicating possible transmission route of oral-faecal transmission. Proper handling with the infected corpse and disposal of human excreta of infected patients were of great importance(
). Thrombi were seen in all six autopsies of SARS-CoV infected patients, with even huge thrombus formation in part of pulmonary vessels. Coagulation function disorders were reported in most of the severe COVID-19 patients, by elevated levels of D-Dimer and prolonged prothrombin time, some of whom ended in disseminated intravascular coagulation( ). This may explain some sudden death of clinical recovery patients and serve as an indication for disease severity. In an autopsy study, the only one patient without usage of corticosteroids demonstrated increased CD3+ lymphocyte than five other specimen treated by corticosteroids ( ). It suggested an inhibition of immune system and a careful usage of corticosteroids in COVID-19 treatment. Much is to be discovered in more 2019-nCoV autopsies.
first reported the pathological characteristics of a patient who died from COVID-19. General observation from raw eyes showed less fibrosis and consolidation, instead more exudative lesions in COVID-19 than SARS. Microscopic examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates, indicating ARDS. Interstitial mononuclear inflammatory infiltrates were dominated by lymphocytes. Multinucleated syncytial cells with atypical enlarged pneumocytes showed viral cytopathic-like changes, without obvious intranuclear or intracytoplasmic viral inclusions. Results from flow cytometric analysis demonstrated that the counts of peripheral CD4+ and CD8 + T cells were substantially reduced, while their status were hyper-activated. It indicated the severe immune injury in later stage of COVID-19, but not by virus direct destruction( ). Based on the public database and single-cell RNA-Seq technique, pathological studies revealed that male donors had a higher ACE2-expressing cell ratio than their female counterparts. The only Asian male specimen has five more times as much as ACE2 expressing on the white and African American donors. This might explain why the 2019-nCov and previous SARS-CoV pandemic were concentrated in the Asian population and a heightened susceptibility of male patients, although more evidence was needed to draw such conclusion
Pathological manifestations of SARS and MERS infected patients may shed lights to control current 2019-nCoV pandemic. Histology examination demonstrated a considerably higher viral load of SARS-CoV RNA in lung and small bowels than other organs of the body, suggesting an reason for manifestation of pneumonia and diarrhea in SARS patients. Living 2019-nCoV was also detected positive in stool specimens and rectal swabs of infected patients, indicating possible transmission route of oral-faecal transmission. Proper handling with the infected corpse and disposal of human excreta of infected patients were of great importance(
). Thrombi were seen in all six autopsies of SARS-CoV infected patients, with even huge thrombus formation in part of pulmonary vessels. Coagulation function disorders were reported in most of the severe COVID-19 patients, by elevated levels of D-Dimer and prolonged prothrombin time, some of whom ended in disseminated intravascular coagulation( ). This may explain some sudden death of clinical recovery patients and serve as an indication for disease severity. In an autopsy study, the only one patient without usage of corticosteroids demonstrated increased CD3+ lymphocyte than five other specimen treated by corticosteroids ( ). It suggested an inhibition of immune system and a careful usage of corticosteroids in COVID-19 treatment. Much is to be discovered in more 2019-nCoV autopsies.
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Treatment
There are currently no vaccine or specific effective antiviral therapies for COVID-19 in general. Thus there is an urgent need for global surveillance of COVID-19 patients. New therapeutic drugs are emerging one after another. However, double-blinded randomized controlled trials with larger sample size are needed to determine the safety and efficacy of these new drugs and guide clinical decision. Medical interventions can be divided into four major categories: general treatment, coronavirus specific treatments, antiviral treatments and others.
General treatments included nutritional interventions, immuno-enhancers and Chinese medicine. Interferon, intravenous gamma-globulin and thymosin were believed to boost our immune system to fight with SARS-CoV and MERS-CoV as well as 2019-nCoV. Chloroquine, an old Chinese medicine for treatment of malaria and autoimmune disease, had demonstrated remarkable inhibition in the spread of SARS-CoV by interfering with ACE2 in Vero E6 cell lines(
). demonstrated that chloroquine functioned at both entry and post-entry stages of the 2019-nCoV infection in Vero E6 cells, as well as an immune-modulating activity that enhanced antiviral effect in vivo. Recent multicenter clinical trails conducted in China have also reported obvious efficacy and acceptable safety in COVID-19 patients by reducing exacerbation of pneumonia, improving radiological findings, promoting a virus negative conversion, and shortening the disease course(
Due to the indispensable role of the S-protein in coronavirus, therapies and vaccine exploration targeting S-protein-ACE2 interaction may be very promising. Previous therapies targeting SARS-CoV and MERS-CoV may accelerate the development of treatment of COVID-19 because of their structure resemblance and genome similarities. The human monoclonal antibody could efficiently neutralize SARS-CoV and inhibit syncytia formation between S-protein and ACE2 expressing cells(
). Appropriate modification of the monoclonal antibody may be effective for treatment of COVID-19. What’s more, potential therapies targeting the renin-angiotensin system, to increase ACE2 expression and inhibit ACE may be developed to treat COVID-19 in the future.
reported a cellular protease TMPRSS2 for 2019-nCoV priming upon entrance into cells and viral spread in the infected host cells. The serine protease inhibitor camostat mesylate against TMPRSS2, can efficiently blocked 2019-nCoV-S-protein-driven cell entry, which could be a promising treatment for 2019-nCoV infection.
There are no effective antiviral treatment for coronavirus infection, even the strong candidates as lopinavir/ritonavir and abidol exhibited no remarkable effect on clinical improvement, day 28 mortality or virus clearance(Chen et al., 2020). Expectation and attention were shifted to “remdesivir” which may be the most potential wide-spectrum drug for antiviral treatment of 2019-nCoV. Remdesivir is an adenosine analogue, which incorporates into novel viral RNA chains and results in pre-mature termination. It is currently under clinical development for the treatment of Ebola virus infection(
). revealed that remdesivir were highly effective and safe in the control of 2019-nCoV infection in Vero E6 cells and Huh-7 cells. A successful appliance of remdesivir on the first 2019-nCoV infected case in the United States when the his clinical status was getting worsen, were recently released( ). Animal experiments also showed superiority of remdesivir over lopinavir/ritonavir combined with interferon-β, by reducing MERS-CoV titers of infected mice and improving the lung tissue damage( The effectiveness and safety of remdesivir can be expected by the clinical trial lead by Dr Bin Cao.
The 2019-nCoV infection is associated with a cytokine storm triggered by over-activated immune system(
) similar to SARS and MERS. The aberrant and excessive immune responses lead to a long-term lung function and structure damage in patients survived from ICU. Ongoing trials of IL-6 antagonist tocilizumab, which shown effective against cytokine release syndrome resulting from CAR-T cell infusion against B cell acute lymphoblastic leukemia, may be expanded to restore T cell counts and treat severe 2019-nCoV infection( ). The available observational studies and meta-analysis of corticosteroid treatment suggested impaired antibody response, increased mortality and secondary infection rates in influenza, increased viraemia and impaired virus clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors( ). Therefore, corticosteroid should not be recommended for treatment of 2019-nCoV, or use on severe patient with special caution. A review on convalescent plasma for treatment of SARS-CoV and severe influenza infection, suggested a reduction in hospital stay and mortality rate, especially when administered early after symptom onset ( ). However, another study demonstrated no significant improvement of convalescent plasma transfusion on survival of Ebola virus infected patients. Possible reasons may be the unknown levels of neutralizing antibodies in convalescent plasma and transfusion timing( ). In terms of vaccine, if any cross-reactive epitopes were identified between 2019-nCoV and SARS-CoV, previous vaccine for SARS-CoV might be re-utilized to facilitate 2019-nCoV vaccine development. We recommend an influenza and Streptococcus pneumoniae vaccination for prophylaxis, especially in elderly adults( ). Both pandemic viruses result in similar respiratory symptoms and hard to distinguish. The 2019-nCoV pandemic initiated in flu season which easy to develop a combination infection of 2019-nCoV and influenza or Streptococcus infection. Vaccination against influenza and Streptococcus pneumonia in vulnerable elderly people with comorbidities are highly cost-effective, which is demonstrated to associate with reductions in the risk of hospitalization and death from all causes during influenza season
There are currently no vaccine or specific effective antiviral therapies for COVID-19 in general. Thus there is an urgent need for global surveillance of COVID-19 patients. New therapeutic drugs are emerging one after another. However, double-blinded randomized controlled trials with larger sample size are needed to determine the safety and efficacy of these new drugs and guide clinical decision. Medical interventions can be divided into four major categories: general treatment, coronavirus specific treatments, antiviral treatments and others.
General treatments included nutritional interventions, immuno-enhancers and Chinese medicine. Interferon, intravenous gamma-globulin and thymosin were believed to boost our immune system to fight with SARS-CoV and MERS-CoV as well as 2019-nCoV. Chloroquine, an old Chinese medicine for treatment of malaria and autoimmune disease, had demonstrated remarkable inhibition in the spread of SARS-CoV by interfering with ACE2 in Vero E6 cell lines(
). demonstrated that chloroquine functioned at both entry and post-entry stages of the 2019-nCoV infection in Vero E6 cells, as well as an immune-modulating activity that enhanced antiviral effect in vivo. Recent multicenter clinical trails conducted in China have also reported obvious efficacy and acceptable safety in COVID-19 patients by reducing exacerbation of pneumonia, improving radiological findings, promoting a virus negative conversion, and shortening the disease course(
Due to the indispensable role of the S-protein in coronavirus, therapies and vaccine exploration targeting S-protein-ACE2 interaction may be very promising. Previous therapies targeting SARS-CoV and MERS-CoV may accelerate the development of treatment of COVID-19 because of their structure resemblance and genome similarities. The human monoclonal antibody could efficiently neutralize SARS-CoV and inhibit syncytia formation between S-protein and ACE2 expressing cells(
). Appropriate modification of the monoclonal antibody may be effective for treatment of COVID-19. What’s more, potential therapies targeting the renin-angiotensin system, to increase ACE2 expression and inhibit ACE may be developed to treat COVID-19 in the future.
reported a cellular protease TMPRSS2 for 2019-nCoV priming upon entrance into cells and viral spread in the infected host cells. The serine protease inhibitor camostat mesylate against TMPRSS2, can efficiently blocked 2019-nCoV-S-protein-driven cell entry, which could be a promising treatment for 2019-nCoV infection.
There are no effective antiviral treatment for coronavirus infection, even the strong candidates as lopinavir/ritonavir and abidol exhibited no remarkable effect on clinical improvement, day 28 mortality or virus clearance(Chen et al., 2020). Expectation and attention were shifted to “remdesivir” which may be the most potential wide-spectrum drug for antiviral treatment of 2019-nCoV. Remdesivir is an adenosine analogue, which incorporates into novel viral RNA chains and results in pre-mature termination. It is currently under clinical development for the treatment of Ebola virus infection(
). revealed that remdesivir were highly effective and safe in the control of 2019-nCoV infection in Vero E6 cells and Huh-7 cells. A successful appliance of remdesivir on the first 2019-nCoV infected case in the United States when the his clinical status was getting worsen, were recently released( ). Animal experiments also showed superiority of remdesivir over lopinavir/ritonavir combined with interferon-β, by reducing MERS-CoV titers of infected mice and improving the lung tissue damage( The effectiveness and safety of remdesivir can be expected by the clinical trial lead by Dr Bin Cao.
The 2019-nCoV infection is associated with a cytokine storm triggered by over-activated immune system(
) similar to SARS and MERS. The aberrant and excessive immune responses lead to a long-term lung function and structure damage in patients survived from ICU. Ongoing trials of IL-6 antagonist tocilizumab, which shown effective against cytokine release syndrome resulting from CAR-T cell infusion against B cell acute lymphoblastic leukemia, may be expanded to restore T cell counts and treat severe 2019-nCoV infection( ). The available observational studies and meta-analysis of corticosteroid treatment suggested impaired antibody response, increased mortality and secondary infection rates in influenza, increased viraemia and impaired virus clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors( ). Therefore, corticosteroid should not be recommended for treatment of 2019-nCoV, or use on severe patient with special caution. A review on convalescent plasma for treatment of SARS-CoV and severe influenza infection, suggested a reduction in hospital stay and mortality rate, especially when administered early after symptom onset ( ). However, another study demonstrated no significant improvement of convalescent plasma transfusion on survival of Ebola virus infected patients. Possible reasons may be the unknown levels of neutralizing antibodies in convalescent plasma and transfusion timing( ). In terms of vaccine, if any cross-reactive epitopes were identified between 2019-nCoV and SARS-CoV, previous vaccine for SARS-CoV might be re-utilized to facilitate 2019-nCoV vaccine development. We recommend an influenza and Streptococcus pneumoniae vaccination for prophylaxis, especially in elderly adults( ). Both pandemic viruses result in similar respiratory symptoms and hard to distinguish. The 2019-nCoV pandemic initiated in flu season which easy to develop a combination infection of 2019-nCoV and influenza or Streptococcus infection. Vaccination against influenza and Streptococcus pneumonia in vulnerable elderly people with comorbidities are highly cost-effective, which is demonstrated to associate with reductions in the risk of hospitalization and death from all causes during influenza season
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