Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
1.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733534

ABSTRACT

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.

2.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Article in English | MEDLINE | ID: covidwho-710376

ABSTRACT

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Betacoronavirus/immunology , Coronavirus Infections/immunology , Interferon Type I/metabolism , Pneumonia, Viral/immunology , Receptors, Immunologic/metabolism , Adolescent , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/genetics , Antigens, Differentiation, T-Lymphocyte/immunology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cohort Studies , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , GPI-Linked Proteins/metabolism , Humans , Interferon Type I/genetics , Interferon Type I/immunology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , RNA-Seq , Receptors, Immunologic/genetics , Receptors, Immunologic/immunology , Severity of Illness Index , Single-Cell Analysis
3.
Med. J. Chin. Peoples Liberation Army ; 5(45): 475-480, 20200528.
Article in Chinese | ELSEVIER | ID: covidwho-701007

ABSTRACT

Objective To provide a basis for further optimizing the diagnosis and treatment strategies of severe and critical corona virus disease 2019 (COVID-19) by investigating and analyzing the epidemiological and clinical characteristics of the death cases. Methods The epidemiological and clinical characteristics of 47 death cases obtained from Huoshenshan Hospital in Whuhan, Hubei Province were retrospectively analyzed. Results All the patients developed initial symptoms in Wuhan. The time from onset to admission was (12.60±5.60) days. Most of them were male (68.09%) with non-nosocomial infection (91.49%), advanced age (>60 years, 89.36%). Over half of the cases (51.06%) reported a history of contact with suspected or confirmed patients, and comorbidity of chronic diseases (70.21%). Multiple organ dysfunction syndrome (MODS) occurred in 29 cases (61.70%) with heart failure (51.06%) and renal failure (36.17%). The main clinical symptoms included fever, fatigue, dyspnea and cough. At admission,most cases were severe (55.32%) or critical (42.55%), and the in-hospital survival was longer for the severe than for the critical (P=0.02). 76.59% of the patients received invasive mechanical ventilation, and they had a longer in-hospital survival than those with non-invasive mechanical ventilation (P<0.05). Conclusions This group of cases occurred during the peak of the COVID-19 outbreak in China, characterized by male, elder and history of chronic diseases. Acute respiratory distress syndrome (ARDS) caused by COVID-19 was responsible for patients' death, and MODS manifestated by heart and kidney failure also implicated in the process. Disease severity and invasive mechanical ventilation were related to in-hospital survival.

4.
Nat Commun ; 11(1): 3410, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-635899

ABSTRACT

COVID-19 is associated with 5.1% mortality. Although the virological, epidemiological, clinical, and management outcome features of COVID-19 patients have been defined rapidly, the inflammatory and immune profiles require definition as they influence pathogenesis and clinical expression of COVID-19. Here we show lymphopenia, selective loss of CD4+ T cells, CD8+ T cells and NK cells, excessive T-cell activation and high expression of T-cell inhibitory molecules are more prominent in severe cases than in those with mild disease. CD8+ T cells in patients with severe disease express high levels of cytotoxic molecules. Histochemical studies of lung tissue from one fatality show sub-anatomical distributions of SARS-CoV-2 RNA and massive infiltration of T cells and macrophages. Thus, aberrant activation and dysregulation of CD8+ T cells occur in patients with severe COVID-19 disease, an effect that might be for pathogenesis of SARS-CoV-2 infection and indicate that immune-based targets for therapeutic interventions constitute a promising treatment for severe COVID-19 patients.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , Biomarkers/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Chemotaxis, Leukocyte , China/epidemiology , Coronavirus Infections/blood , Coronavirus Infections/virology , Cytokines/blood , Female , Humans , Inflammation , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Leukocyte Count , Lung/immunology , Lung/virology , Lymphocyte Activation , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology
5.
Cell Metab ; 32(2): 188-202.e5, 2020 08 04.
Article in English | MEDLINE | ID: covidwho-612608

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented threat to global public health. Herein, we utilized a combination of targeted and untargeted tandem mass spectrometry to analyze the plasma lipidome and metabolome in mild, moderate, and severe COVID-19 patients and healthy controls. A panel of 10 plasma metabolites effectively distinguished COVID-19 patients from healthy controls (AUC = 0.975). Plasma lipidome of COVID-19 resembled that of monosialodihexosyl ganglioside (GM3)-enriched exosomes, with enhanced levels of sphingomyelins (SMs) and GM3s, and reduced diacylglycerols (DAGs). Systems evaluation of metabolic dysregulation in COVID-19 was performed using multiscale embedded differential correlation network analyses. Using exosomes isolated from the same cohort, we demonstrated that exosomes of COVID-19 patients with elevating disease severity were increasingly enriched in GM3s. Our work suggests that GM3-enriched exosomes may partake in pathological processes related to COVID-19 pathogenesis and presents the largest repository on the plasma lipidome and metabolome distinct to COVID-19.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/pathology , Exosomes/metabolism , G(M3) Ganglioside/blood , Gangliosides/blood , Pneumonia, Viral/blood , Pneumonia, Viral/pathology , Adult , Aged , Betacoronavirus , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Diglycerides/blood , Female , Humans , Male , Metabolome/physiology , Metabolomics/methods , Middle Aged , Pandemics , Sphingomyelins/blood , Tandem Mass Spectrometry , Young Adult
6.
J Clin Lab Anal ; : e23415, 2020 Jun 02.
Article in English | MEDLINE | ID: covidwho-505885

ABSTRACT

BACKGROUND: This study aimed to investigate clinical characteristics, laboratory indexes, treatment regimens, and short-term outcomes of severe and critical coronavirus disease 2019 (COVID-19) patients. METHODS: One hundred and sixty one consecutive severe and critical COVID-19 patients admitted in intensive care unit (ICU) were retrospectively reviewed in this multicenter study. Demographic features, medical histories, clinical symptoms, lung computerized tomography (CT) findings, and laboratory indexes on admission were collected. Post-admission complications, treatment regimens, and clinical outcomes were also documented. RESULTS: The mean age was 59.38 ± 16.54 years, with 104 (64.60%) males and 57 (35.40%) females. Hypertension (44 [27.33%]) and diabetes were the most common medical histories. Fever (127 [78.88%]) and dry cough (111 [68.94%]) were the most common symptoms. Blood routine indexes, hepatic and renal function indexes, and inflammation indexes were commonly abnormal. Acute respiratory distress syndrome (ARDS) was the most common post-admission complication (69 [42.86%]), followed by electrolyte disorders (48 [29.81%]), multiple organ dysfunction (MODS) (37 [22.98%]), and hypoproteinemia (36 [22.36%]). The most commonly used antiviral drug was lopinavir/ritonavir tablet. 50 (31.06%) patients died, while 78 (48.45%) patients healed and discharged, and the last 33 (20.50%) patients remained in hospital. Besides, the mean hospital stay of deaths was 21.66 ± 11.18 days, while the mean hospital stay of discharged patients was 18.42 ± 12.77 days. Furthermore, ARDS (P < .001) and MODS (P = .008) correlated with increased mortality rate. CONCLUSION: Severe and critical COVID-19 presents with high mortality rate, and occurrence of ARDS or MODS greatly increases its mortality risk.

7.
J Infect Dis ; 2020 Jun 03.
Article in English | MEDLINE | ID: covidwho-505538

ABSTRACT

The current discharge criteria for COVID-19 require that patients have two consecutive negative results for RT-PCR detection. Here, we observed that recurrently positive RT-PCR test results in patients with three consecutive negative results (3xNegRPos, 5.4%) were significantly decreased compared with those in patients with two consecutive negative results (2xNegRPos, 20.6%); such patients reported positive RT-PCR test results within 1 to 12 days after meeting the discharge criteria. These results confirmed that many recovered patients could show a positive RT-PCR test result, and most of these patients could be identified by an additional RT-PCR test prior to discharge.

8.
Nature ; 583(7815): 286-289, 2020 07.
Article in English | MEDLINE | ID: covidwho-210764

ABSTRACT

The current outbreak of coronavirus disease-2019 (COVID-19) poses unprecedented challenges to global health1. The new coronavirus responsible for this outbreak-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-shares high sequence identity to SARS-CoV and a bat coronavirus, RaTG132. Although bats may be the reservoir host for a variety of coronaviruses3,4, it remains unknown whether SARS-CoV-2 has additional host species. Here we show that a coronavirus, which we name pangolin-CoV, isolated from a Malayan pangolin has 100%, 98.6%, 97.8% and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S proteins, respectively. In particular, the receptor-binding domain of the S protein of pangolin-CoV is almost identical to that of SARS-CoV-2, with one difference in a noncritical amino acid. Our comparative genomic analysis suggests that SARS-CoV-2 may have originated in the recombination of a virus similar to pangolin-CoV with one similar to RaTG13. Pangolin-CoV was detected in 17 out of the 25 Malayan pangolins that we analysed. Infected pangolins showed clinical signs and histological changes, and circulating antibodies against pangolin-CoV reacted with the S protein of SARS-CoV-2. The isolation of a coronavirus from pangolins that is closely related to SARS-CoV-2 suggests that these animals have the potential to act as an intermediate host of SARS-CoV-2. This newly identified coronavirus from pangolins-the most-trafficked mammal in the illegal wildlife trade-could represent a future threat to public health if wildlife trade is not effectively controlled.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Eutheria/virology , Evolution, Molecular , Genome, Viral/genetics , Sequence Homology, Nucleic Acid , Animals , Betacoronavirus/classification , China , Chiroptera/virology , Chlorocebus aethiops , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/transmission , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Disease Reservoirs/virology , Genomics , Host Specificity , Humans , Lung/pathology , Lung/virology , Malaysia , Nucleocapsid Proteins/genetics , Pandemics , Phylogeny , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Polymerase Chain Reaction , Recombination, Genetic , Sequence Alignment , Sequence Analysis, RNA , Spike Glycoprotein, Coronavirus/genetics , Vero Cells , Viral Envelope Proteins/genetics , Viral Matrix Proteins/genetics , Zoonoses/transmission , Zoonoses/virology
9.
J Am Soc Nephrol ; 31(7): 1387-1397, 2020 07.
Article in English | MEDLINE | ID: covidwho-209419

ABSTRACT

BACKGROUND: Reports indicate that those most vulnerable to developing severe coronavirus disease 2019 (COVID-19) are older adults and those with underlying illnesses, such as diabetes mellitus, hypertension, or cardiovascular disease, which are common comorbidities among patients undergoing maintenance hemodialysis. However, there is limited information about the clinical characteristics of hemodialysis patients with COVID-19 or about interventions to control COVID-19 in hemodialysis centers. METHODS: We collected data retrospectively through an online registration system that includes all patients receiving maintenance hemodialysis at 65 centers in Wuhan, China. We reviewed epidemiologic and clinical data of patients with laboratory-confirmed COVID-19 between January 1, 2020 and March 10, 2020. RESULTS: Of 7154 patients undergoing hemodialysis, 154 had laboratory-confirmed COVID-19. The mean age of the 131 patients in our analysis was 63.2 years; 57.3% were men. Many had underlying comorbidities, with cardiovascular disease (including hypertension) being the most common (68.7%). Only 51.9% of patients manifested fever; 21.4% of infected patients were asymptomatic. The most common finding on chest computed tomography (CT) was ground-grass or patchy opacity (82.1%). After initiating comprehensive interventions-including entrance screening of body temperature and symptoms, universal chest CT and blood tests, and other measures-new patients presenting with COVID-19 peaked at 10 per day on January 30, decreasing to 4 per day on February 11. No new cases occurred between February 26 and March 10, 2020. CONCLUSIONS: We found that patients receiving maintenance hemodialysis were susceptible to COVID-19 and that hemodialysis centers were high-risk settings during the epidemic. Increasing prevention efforts, instituting universal screening, and isolating patients with COVID-19 and directing them to designated hemodialysis centers were effective in preventing the spread of COVID-19 in hemodialysis centers.


Subject(s)
Coronavirus Infections/epidemiology , Disease Susceptibility/epidemiology , Kidney Failure, Chronic/epidemiology , Pneumonia, Viral/epidemiology , Registries , Renal Dialysis/methods , Age Factors , Aged , Chi-Square Distribution , China/epidemiology , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/therapy , Female , Humans , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/therapy , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/therapy , Prevalence , Radiography, Thoracic/methods , Renal Dialysis/statistics & numerical data , Retrospective Studies , Risk Assessment , Sex Factors , Statistics, Nonparametric , Survival Analysis , Tomography, X-Ray Computed/methods
11.
Preprint | medRxiv | ID: ppmedrxiv-20034876

ABSTRACT

Background Since late December 2019, the outbreak of the novel coronavirus disease, COVID-19, that began in Wuhan, has become endemic in China and more than 100 countries and regions in the world. There is no report about the prevalence of COVID-19 in CML patients untill now. We aimed to describe the clinical course, outcomes of CML patients with COVID-19 and prevalence of COVID-19 in CML patients. Methods In this multi-center survey, cross-sectional survey, observational study, the clinical data of CML patients with COVID-19 in each center were collected. Simultaneously, an online survey was conducted for information about the CML patients under the management at each center by asking the CML patients to complete a questionnaire,from February 15, 2020 to February 21, 2020. The questionnaire includes demographic data, place of residence, smoking status, CML diagnosis and treatment, comorbidities, combined medications, epidemiological history, symptoms(fever, cough, shortness of breath, etc) during the epidemic. Additional clinical data was collected on respondents suspected or confirmed to have COVID-19. We described and analyzed the prevalence of COVID-19 in CML patients, and focus on the clinical characteristics and outcomes of COVID-19 patients. Data were compared between the CML patients with optimal response and those with non-optimal response. The primary outcome was prevalence of COVID-19 in CML patients, as of Feb 21, 2020. Secondary outcomes included the history of epidemiology of CML patients, the clinical characteristics and outcomes of CML patients with COVID-19 . Findings Of 392 respondents, 223( 56.9%) were males, and 240( 61.2%) were 50 years or younger. Only 10 patients took drugs irregularly due to the influence of the epidemic because of traffic control, pharmacies unable to operate normally, etc. In the history of epidemiology, there were 4 patients with definite contact with COVID-19, of which 3 were remote contact and 1 was close contact. 12 respondents had fever, cough or shortness of breath during the epidemic, 1 case (common type) was confirmed with COVID-19 and cured after treatment. 1 patient was clinically diagnosed and succumbed. 1 of 299 (0.3%) patients with an optimal response was diagnosed with COVID-19. Of the 50 patients who failed to respond to CML treatment or had a poor response, 1 patient (2%) had a clinical diagnosis of COVID-19. Interpretation While the 392 CML respondents required regular referrals to hospitals, they did not have much contact with COVID-19 patients during the outbreak. Patients who failed to achieved an optimal response to CML therapy appear more likely to have a symptomatic infection with SARS-CoV-2. Older patients with comorbidities are at increased risk of death.

12.
Preprint | medRxiv | ID: ppmedrxiv-20023655

ABSTRACT

Pneumonia patients of 2019-ncov in latent period are not easy to be effectively quarantined, but there is evidence that they have strong infectious ability. Here, the infectious ability of patients during the latent period is slightly less than that of the infected patients was assumed. We established a new SEIR propagation dynamics model, that considered the weak transmission ability of the incubation period, the variation of the incubation period length, and the government intervention measures to track and isolate comprehensively. Based on the raw epidemic data of China from January 23, 2020 to February 10, 2020, the dynamic parameters of the new present SEIR model are fitted. Through the Euler integration algorithm to solve the model, the effect of infectious ability of incubation patients on the theoretical estimation of the present SEIR model was analyzed, and the occurrence time of peak number in China was predicted.

13.
Preprint | medRxiv | ID: ppmedrxiv-20023630

ABSTRACT

Background: Corona Virus Disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan city and rapidly spread throughout China since late December 2019. Crude case fatality ratio (CFR) with dividing the number of known deaths by the number of confirmed cases does not represent the true CFR and might be off by orders of magnitude. We aim to provide a precise estimate of the CFR of COVID-19 using statistical models at the early stage of the epidemic. Methods: We extracted data from the daily released epidemic report published by the National Health Commission P. R. China from 20 Jan 2020, to 1 March 2020. Competing risk model was used to obtain the cumulative hazards for death, cure, and cure-death hazard ratio. Then the CFR was estimated based on the slope of the last piece in joinpoint regression model, which reflected the most recent trend of the epidemic. Results: As of 1 March 2020, totally 80,369 cases were diagnosed as COVID-19 in China. The CFR of COVID-19 were estimated to be 70.9% (95% CI: 66.8%-75.6%) during Jan 20-Feb 2, 20.2% (18.6%-22.1%) during Feb 3-14, 6.9% (6.4%-7.4%) during Feb 15-23, 1.5% (1.4%-1.6%) during Feb 24-March 1 in Hubei province, and 20.3% (17.0%-25.3%) during Jan 20-28, 1.9% (1.8%-2.1%) during Jan 29-Feb 12, 0.9% (0.8%-1.1%) during Feb 13-18, 0.4% (0.4%-0.5%) during Feb 19-March 1 in other areas of China, respectively. Conclusions: Based on analyses of public data, we found that the CFR in Hubei was much higher than that of other regions in China, over 3 times in all estimation. The CFR would follow a downwards trend based on our estimation from recently released data. Nevertheless, at early stage of outbreak, CFR estimates should be viewed cautiously because of limited data source on true onset and recovery time.

14.
Preprint | bioRxiv | ID: ppbiorxiv-951335

ABSTRACT

The outbreak of 2019-nCoV in the central Chinese city of Wuhan at the end of 2019 poses unprecedent public health challenges to both China and the rest world1. The new coronavirus shares high sequence identity to SARS-CoV and a newly identified bat coronavirus2. While bats may be the reservoir host for various coronaviruses, whether 2019-nCoV has other hosts is still ambiguous. In this study, one coronavirus isolated from Malayan pangolins showed 100%, 98.2%, 96.7% and 90.4% amino acid identity with 2019-nCoV in the E, M, N and S genes, respectively. In particular, the receptor-binding domain of the S protein of the Pangolin-CoV is virtually identical to that of 2019-nCoV, with one amino acid difference. Comparison of available genomes suggests 2019-nCoV might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus. Infected pangolins showed clinical signs and histopathological changes, and the circulating antibodies reacted with the S protein of 2019-nCoV. The isolation of a coronavirus that is highly related to 2019-nCoV in the pangolins suggests that these animals have the potential to act as the intermediate host of 2019-nCoV. The newly identified coronavirus in the most-trafficked mammal could represent a continuous threat to public health if wildlife trade is not effectively controlled.

15.
Preprint | bioRxiv | ID: ppbiorxiv-954628

ABSTRACT

The outbreak of 2019-nCoV pneumonia (COVID-19) in the city of Wuhan, China has resulted in more than 70,000 laboratory confirmed cases, and recent studies showed that 2019-nCoV (SARS-CoV-2) could be of bat origin but involve other potential intermediate hosts. In this study, we assembled the genomes of coronaviruses identified in sick pangolins. The molecular and phylogenetic analyses showed that pangolin Coronaviruses (pangolin-CoV) are genetically related to both the 2019-nCoV and bat Coronaviruses but do not support the 2019-nCoV arose directly from the pangolin-CoV. Our study also suggested that pangolin be natural host of Betacoronavirus, with a potential to infect humans. Large surveillance of coronaviruses in pangolins could improve our understanding of the spectrum of coronaviruses in pangolins. Conservation of wildlife and limits of the exposures of humans to wildlife will be important to minimize the spillover risks of coronaviruses from wild animals to humans.

16.
Preprint | bioRxiv | ID: ppbiorxiv-956581

ABSTRACT

The recent emergence of a novel coronavirus associated with an ongoing outbreak of pneumonia (Covid-2019) resulted in infections of more than 72,000 people and claimed over 1,800 lives. Coronavirus spike (S) glycoprotein trimers promote entry into cells and are the main target of the humoral immune response. We show here that SARS-CoV-2 S mediates entry in VeroE6 cells and in BHK cells transiently transfected with human ACE2, establishing ACE2 as a functional receptor for this novel coronavirus. We further demonstrate that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, which correlates with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and other SARS-related CoVs. We determined a cryo-electron microscopy structure of the SARS-CoV-2 S ectodomain trimer, demonstrating spontaneous opening of the receptor-binding domain, and providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal sera potently inhibited SARS-CoV-2 S-mediated entry into target cells, thereby indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

17.
Preprint | bioRxiv | ID: ppbiorxiv-957118

ABSTRACT

Using incipient lines of the Collaborative Cross (CC), a murine genetic reference population, we previously identified a quantitative trait loci (QTL) associated with low SARS-CoV titer. In this study, we integrated sequence information and RNA expression of genes within the QTL to identify mucin 4 (Muc4) as a high priority candidate for controlling SARS-CoV titer in the lung. To test this hypothesis, we infected Muc4-/- mice and found that female, but not male, Muc4-/- mice developed more weight loss and disease following infection with SARS-CoV. Female Muc4-/- mice also had more difficulty breathing despite reduced lung pathology; however, no change in viral titers was observed. Comparing across viral families, studies with chikungunya virus, a mosquito-borne arthralgic virus, suggests that Muc4s impact on viral pathogenesis may be widespread. Although not confirming the original titer QTL, our data identifies a role for Muc4 in the SARS-CoV disease and viral pathogenesis. ImportanceGiven the recent emergence of SARS-CoV-2, this work suggest that Muc4 expression plays a protective role in female mice not conserved in male mice following SARS-CoV infection. With the SARS-CoV-2 outbreak continuing, treatments that modulate or enhance Muc4 activity may provide an avenue for treatment and improved outcomes. In addition, the work highlights the importance of studying host factors including host genetics and biological sex as key parameters influencing infection and disease outcomes.

18.
Preprint | bioRxiv | ID: ppbiorxiv-950253

ABSTRACT

To explore potential intermediate host of a novel coronavirus is vital to rapidly control continuous COVID-19 spread. We found genomic and evolutionary evidences of the occurrence of 2019-nCoV-like coronavirus (named as Pangolin-CoV) from dead Malayan Pangolins. Pangolin-CoV is 91.02% and 90.55% identical at the whole genome level to 2019-nCoV and BatCoV RaTG13, respectively. Pangolin-CoV is the lowest common ancestor of 2019-nCoV and RaTG13. The S1 protein of Pangolin-CoV is much more closely related to 2019-nCoV than RaTG13. Five key amino-acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and 2019-nCoV but four amino-acid mutations occur in RaTG13. It indicates Pangolin-CoV has similar pathogenic potential to 2019-nCoV, and would be helpful to trace the origin and probable intermediate host of 2019-nCoV.

19.
Preprint | bioRxiv | ID: ppbiorxiv-951723

ABSTRACT

SARS-CoV-2 and SARS-CoV share a common human receptor ACE2. Protein-protein interaction structure modeling indicates that spike-RBD of the two viruses also has similar overall binding conformation and binding free energy to ACE2. In vitro assays using recombinant ACE2 proteins and ACE2 expressing cells confirmed the two coronaviruses similar binding affinities to ACE2. The above studies provide experimental supporting evidences and possible explanation for the high transmissibility observed in the SARS-CoV-2 outbreak. Potent ACE2-blocking SARS-CoV neutralizing antibodies showed limited cross-binding and neutralizing activities to SARS-CoV-2. ACE2-non-blocking SARS-CoV RBD antibodies, though with weaker neutralizing activities against SARS-CoV, showed positive cross-neutralizing activities to SARS-CoV-2 with an unknown mechanism. These findings suggest a trade-off between the efficacy and spectrum for therapeutic antibodies to different coronaviruses, and hence highlight the possibilities and challenges in developing broadly protecting antibodies and vaccines against SARS-CoV-2 and its future mutants.

20.
Preprint | bioRxiv | ID: ppbiorxiv-952879

ABSTRACT

A novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 [A] resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-[A] crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

SELECTION OF CITATIONS
SEARCH DETAIL