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Co-infections with pathogens and secondary bacterial infections play significant roles during the pandemic coronavirus disease 2019 (COVID-19) pathogenetic process, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Notably, co-infections with Streptococcus pneumoniae (S. pneumoniae), as a major Gram-positive pathogen causing pneumonia or meningitis, severely threaten the diagnosis, therapy, and prognosis of COVID-19 worldwide. Accumulating evidences have emerged indicating that S. pneumoniae evolves multiple virulence factors, including pneumolysin (PLY) and sortase A (SrtA), which have been extensively explored as alternative anti-infection targets. In our study, natural flavonoid kaempferol was identified as a potential candidate drug for infection therapeutics via anti-virulence mechanisms. We found that kaempferol could interfere with the pore-forming activity of PLY by engaging with catalytic active sites and consequently inhibit PLY-mediated cytotoxicity. Additionally, exposed to kaempferol significantly reduced the SrtA peptidase activity by occupying the active sites of SrtA. Further, the biofilms formation and bacterial adhesion to the host cells could be significantly thwarted by kaempferol incubation. In vivo infection model by S. pneumoniae highlighted that kaempferol oral administration exhibited notable treatment benefits, as evidenced by decreased bacterial burden, suggesting that kaempferol has tremendous potential to attenuate S. pneumoniae pathogenicity. Scientifically, our study implies that kaempferol is a promising therapeutic option by targeting bacterial virulence factors.
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Mathematical models have played an important role in the management of the coronavirus disease 2019 (COVID-19) pandemic. The aim of this review is to describe the use of COVID-19 mathematical models, their classification, and the advantages and disadvantages of different types of models. We conducted subject heading searches of PubMed and China National Knowledge Infrastructure with the terms "COVID-19," "Mathematical Statistical Model," "Model," "Modeling," "Agent-based Model," and "Ordinary Differential Equation Model" and classified and analyzed the scientific literature retrieved in the search. We categorized the models as data-driven or mechanism-driven. Data-driven models are mainly used for predicting epidemics, and have the advantage of rapid assessment of disease instances. However, their ability to determine transmission mechanisms is limited. Mechanism-driven models include ordinary differential equation (ODE) and agent-based models. ODE models are used to estimate transmissibility and evaluate impact of interventions. Although ODE models are good at determining pathogen transmission characteristics, they are less suitable for simulation of early epidemic stages and rely heavily on availability of first-hand field data. Agent-based models consider influences of individual differences, but they require large amounts of data and can take a long time to develop fully. Many COVID-19 mathematical modeling studies have been conducted, and these have been used for predicting trends, evaluating interventions, and calculating pathogen transmissibility. Successful infectious disease modeling requires comprehensive considerations of data, applications, and purposes.
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Background: Human immunodeficiency virus (HIV) is a single-stranded RNA virus that can weaken the body's cellular and humoral immunity and is a serious disease without specific drug management and vaccine. This study aimed to evaluate the epidemiologic characteristics and transmissibility of HIV. Methods: Data on HIV follow-up were collected in Nanning City, Guangxi Zhuang Autonomous, China. An HIV transmission dynamics model was built to simulate the transmission of HIV and estimate its transmissibility by comparing the effective reproduction number (Reff ) at different stages: the rapid growth period from January 2001 to March 2005, slow growth period from April 2005 to April 2011, and the plateau from May 2011 to December 2019 of HIV in Nanning City. Results: High-risk areas of HIV prevalence in Nanning City were mainly concentrated in suburbs. Furthermore, high-risk groups were those of older age, with lower income, and lower education levels. The Reff in each stage (rapid growth, slow growth, and plateau) were 2.74, 1.62, and 1.15, respectively, which suggests the transmissibility of HIV in Nanning City has declined and prevention and control measures have achieved significant results. Conclusion: Over the past 20 years, the HIV incidence in Nanning has remained at a relatively high level, but its development trend has been curbed. Transmissibility was reduced from 2.74 to 1.15. Therefore, the prevention and treatment measures in Nanning City have achieved significant improvement.
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HIV Infections , Basic Reproduction Number , China/epidemiology , HIV , HIV Infections/epidemiology , HumansABSTRACT
The article aims to estimate and forecast the transmissibility of shigellosis and explore the association of meteorological factors with shigellosis. The mathematical model named Susceptible–Exposed–Symptomatic/Asymptomatic–Recovered–Water/Food (SEIARW) was used to explore the feature of shigellosis transmission based on the data of Wuhan City, China, from 2005 to 2017. The study applied effective reproduction number (Reff) to estimate the transmissibility. Daily meteorological data from 2008 to 2017 were used to determine Spearman's correlation with reported new cases and Reff. The SEIARW model fit the data well (χ2 = 0.00046, p > 0.999). The simulation results showed that the reservoir-to-person transmission of the shigellosis route has been interrupted. The Reff would be reduced to a transmission threshold of 1.00 (95% confidence interval (CI) 0.82–1.19) in 2035. Reducing the infectious period to 11.25 days would also decrease the value of Reff to 0.99. There was a significant correlation between new cases of shigellosis and atmospheric pressure, temperature, wind speed and sun hours per day. The correlation coefficients, although statistically significant, were very low (<0.3). In Wuhan, China, the main transmission pattern of shigellosis is person-to-person. Meteorological factors, especially daily atmospheric pressure and temperature, may influence the epidemic of shigellosis.
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BACKGROUND: Reaching optimal vaccination rates is an essential public health strategy to control the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to simulate the optimal vaccination strategy to control the disease by developing an age-specific model based on the current transmission patterns of COVID-19 in Wuhan City, China. METHODS: We collected two indicators of COVID-19, including illness onset data and age of confirmed case in Wuhan City, from December 2, 2019, to March 16, 2020. The reported cases were divided into four age groups: group 1, ≤ 14 years old; group 2, 15 to 44 years old; group 3, 44 to 64 years old; and group 4, ≥ 65 years old. An age-specific susceptible-exposed-symptomatic-asymptomatic-recovered/removed model was developed to estimate the transmissibility and simulate the optimal vaccination strategy. The effective reproduction number (Reff) was used to estimate the transmission interaction in different age groups. RESULTS: A total of 47 722 new cases were reported in Wuhan City from December 2, 2019, to March 16, 2020. Before the travel ban of Wuhan City, the highest transmissibility was observed among age group 2 (Reff = 4.28), followed by group 2 to 3 (Reff = 2.61), and group 2 to 4 (Reff = 1.69). China should vaccinate at least 85% of the total population to interrupt transmission. The priority for controlling transmission should be to vaccinate 5% to 8% of individuals in age group 2 per day (ultimately vaccinated 90% of age group 2), followed by 10% of age group 3 per day (ultimately vaccinated 90% age group 3). However, the optimal vaccination strategy for reducing the disease severity identified individuals ≥ 65 years old as a priority group, followed by those 45-64 years old. CONCLUSIONS: Approximately 85% of the total population (nearly 1.2 billion people) should be vaccinated to build an immune barrier in China to safely consider removing border restrictions. Based on these results, we concluded that 90% of adults aged 15-64 years should first be vaccinated to prevent transmission in China.
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COVID-19 , Adolescent , Adult , Aged , China , Cities , Humans , Middle Aged , SARS-CoV-2 , Vaccination , Young AdultABSTRACT
INTRODUCTION: Vaccination booster shots are completely necessary for controlling breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China. The study aims to estimate effectiveness of booster vaccines for high-risk populations (HRPs). METHODS: A vaccinated Susceptible-Exposed-Symptomatic-Asymptomatic-Recovered/Removed (SEIAR) model was developed to simulate scenarios of effective reproduction number (R eff ) from 4 to 6. Total number of infectious and asymptomatic cases were used to evaluated vaccination effectiveness. RESULTS: Our model showed that we could not prevent outbreaks when covering 80% of HRPs with booster unless R eff =4.0 or the booster vaccine had efficacy against infectivity and susceptibility of more than 90%. The results were consistent when the outcome index was confirmed cases or asymptomatic cases. CONCLUSIONS: An ideal coronavirus disease 2019 (COVID-19) booster vaccination strategy for HRPs would be expected to reach the initial goal to control the transmission of the Delta variant in China. Accordingly, the recommendation for the COVID-19 booster vaccine should be implemented in HRPs who are already vaccinated and could prevent transmission to other groups.
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OBJECTIVE: To perform a systematic review and meta-analysis evaluating the efficacy of adjuvant human papillomavirus (HPV) vaccination in preventing recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical excision. DATA SOURCES: Electronic databases (Cochrane, PubMed, EMBASE, MEDLINE, Scopus, and ClinicalTrials.gov) were searched for studies comparing surgical excision alone to surgical excision with adjuvant HPV vaccination for CIN 2 or greater. Studies published from January 1990 to January 2019 were included. METHODS: A total of 5,901 studies were reviewed. The primary outcomes evaluated included: recurrence of CIN 2 or greater, CIN 1 or greater, and HPV 16,18 associated CIN within 6-48 months. We used Covidence software to assist with screening, and meta-analysis was performed using Review Manager. TABULATION, INTEGRATION, AND RESULTS: Six studies met inclusion criteria and were included in the final analysis. In total 2,984 women were included; 1,360 (45.6%) received adjuvant HPV vaccination after surgical excision, and 1,624 (54.4%) received either placebo or surgical management alone for CIN 2 or greater. Recurrence of CIN 2 or greater occurred within 6-48 months in 115 women (3.9%) overall; however, recurrence was significantly lower for vaccinated women: 26 of 1,360 women (1.9%) vs 89 of 1,624 unvaccinated women (5.9%) (relative risk [RR] 0.36 95% CI 0.23-0.55). The risk of CIN 1 or greater was also significantly lower with adjuvant HPV vaccination, occurring in 86 of 1,360 vaccinated women (6.3%) vs 157 of 1,624 unvaccinated women (9.7%) (RR 0.67 95% CI 0.52-0.85). Thirty-five women developed recurrent CIN 2 or greater lesions specific to HPV 16,18; nine received adjuvant vaccination (0.9%) vs 26 who were unvaccinated (2.0%) (RR 0.41 95% CI 0.20-0.85). CONCLUSION: Adjuvant HPV vaccination in the setting of surgical excision for CIN 2 or greater is associated with a reduced risk of recurrent cervical dysplasia overall and a reduction in the risk of recurrent lesions caused by the most oncogenic strains (HPV 16,18). Human papillomavirus vaccination should therefore be considered for adjuvant treatment in patients undergoing surgical excision for CIN 2 or greater. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019123786.
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Neoplasm Recurrence, Local/prevention & control , Papillomavirus Infections/complications , Papillomavirus Vaccines/therapeutic use , Uterine Cervical Dysplasia/drug therapy , Uterine Cervical Neoplasms/drug therapy , Adult , Chemotherapy, Adjuvant , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/virology , Papillomavirus Infections/virology , Treatment Outcome , Uterine Cervical Neoplasms/surgery , Uterine Cervical Neoplasms/virology , Young Adult , Uterine Cervical Dysplasia/surgery , Uterine Cervical Dysplasia/virologyABSTRACT
BACKGROUND: During the period of the coronavirus disease 2019 (COVID-19) outbreak, strong intervention measures, such as lockdown, travel restriction, and suspension of work and production, may have curbed the spread of other infectious diseases, including natural focal diseases. In this study, we aimed to study the impact of COVID-19 prevention and control measures on the reported incidence of natural focal diseases (brucellosis, malaria, hemorrhagic fever with renal syndrome [HFRS], dengue, severe fever with thrombocytopenia syndrome [SFTS], rabies, tsutsugamushi and Japanese encephalitis [JE]). METHODS: The data on daily COVID-19 confirmed cases and natural focal disease cases were collected from Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial CDC). We described and compared the difference between the incidence in 2020 and the incidence in 2015-2019 in four aspects: trend in reported incidence, age, sex, and urban and rural distribution. An autoregressive integrated moving average (ARIMA) (p, d, q) × (P, D, Q)s model was adopted for natural focal diseases, malaria and severe fever with thrombocytopenia syndrome (SFTS), and an ARIMA (p, d, q) model was adopted for dengue. Nonparametric tests were used to compare the reported and the predicted incidence in 2020, the incidence in 2020 and the previous 4 years, and the difference between the duration from illness onset date to diagnosed date (DID) in 2020 and in the previous 4 years. The determination coefficient (R2) was used to evaluate the goodness of fit of the model simulation. RESULTS: Natural focal diseases in Jiangsu Province showed a long-term seasonal trend. The reported incidence of natural focal diseases, malaria and dengue in 2020 was lower than the predicted incidence, and the difference was statistically significant (P < 0.05). The reported incidence of brucellosis in July, August, October and November 2020, and SFTS in May to November 2020 was higher than that in the same period in the previous 4 years (P < 0.05). The reported incidence of malaria in April to December 2020, HFRS in March, May and December 2020, and dengue in July to November 2020 was lower than that in the same period in the previous 4 years (P < 0.05). In males, the reported incidence of malaria in 2020 was lower than that in the previous 4 years, and the reported incidence of dengue in 2020 was lower than that in 2017-2019. The reported incidence of malaria in the 20-60-year age group was lower than that in the previous 4 years; the reported incidence of dengue in the 40-60-year age group was lower than that in 2016-2018. The reported cases of malaria in both urban and rural areas were lower than in the previous 4 years. The DID of brucellosis and SFTS in 2020 was shorter than that in 2015-2018; the DID of tsutsugamushi in 2020 was shorter than that in the previous 4 years. CONCLUSIONS: Interventions for COVID-19 may help control the epidemics of natural focal diseases in Jiangsu Province. The reported incidence of natural focal diseases, especially malaria and dengue, decreased during the outbreak of COVID-19 in 2020. COVID-19 prevention and control measures had the greatest impact on the reported incidence of natural focal diseases in males and people in the 20-60-year age group.
Subject(s)
Brucellosis/epidemiology , COVID-19/prevention & control , Dengue/epidemiology , Malaria/epidemiology , Adult , Age Distribution , Aged , COVID-19/epidemiology , China/epidemiology , Disease Outbreaks , Female , Humans , Incidence , Male , Middle Aged , Physical Distancing , Severe Fever with Thrombocytopenia Syndrome/epidemiology , Travel/statistics & numerical data , Young AdultABSTRACT
Background: It is much valuable to evaluate the comparative effectiveness of the coronavirus disease 2019 (COVID-19) prevention and control in the non-pharmacological intervention phase of the pandemic across countries and identify useful experiences that could be generalized worldwide. Methods: In this study, we developed a susceptible-exposure-infectious-asymptomatic-removed (SEIAR) model to fit the daily reported COVID-19 cases in 160 countries. The time-varying reproduction number (R t ) that was estimated through fitting the mathematical model was adopted to quantify the transmissibility. We defined a synthetic index (I AC ) based on the value of R t to reflect the national capability to control COVID-19. Results: The goodness-of-fit tests showed that the SEIAR model fitted the data of the 160 countries well. At the beginning of the epidemic, the values of R t of countries in the European region were generally higher than those in other regions. Among the 160 countries included in the study, all European countries had the ability to control the COVID-19 epidemic. The Western Pacific Region did best in continuous control of the epidemic, with a total of 73.76% of countries that can continuously control the COVID-19 epidemic, while only 43.63% of the countries in the European Region continuously controlled the epidemic, followed by the Region of Americas with 52.53% of countries, the Southeast Asian Region with 48% of countries, the African Region with 46.81% of countries, and the Eastern Mediterranean Region with 40.48% of countries. Conclusion: Large variations in controlling the COVID-19 epidemic existed across countries. The world could benefit from the experience of some countries that demonstrated the highest containment capabilities.
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Control measures during the coronavirus disease 2019 (COVID-19) outbreak may have limited the spread of infectious diseases. This study aimed to analyse the impact of COVID-19 on the spread of hand, foot, and mouth disease (HFMD) in China. A mathematical model was established to fit the reported data of HFMD in six selected cities in mainland China from 2015 to 2020. The absolute difference (AD) and relative difference (RD) between the reported incidence in 2020, and simulated maximum, minimum, or median incidence of HFMD in 2015-2019 were calculated. The incidence and Reff of HFMD have decreased in six selected cities since the outbreak of COVID-19, and in the second half of 2020, the incidence and Reff of HFMD have rebounded. The results show that the total attack rate (TAR) in 2020 was lower than the maximum, minimum, and median TAR fitted in previous years in six selected cities (except Changsha city). For the maximum, median, minimum fitted TAR, the range of RD (%) is 42•20-99•20%, 36•35-98•41% 48•35-96•23% (except Changsha city) respectively. The preventive and control measures of COVID-19 have significantly contributed to the containment of HFMD transmission.
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A novel coronavirus (SARS-CoV-2) has spread worldwide and led to high disease burden around the world. This study aimed to explore the key parameters of SARS-CoV-2 infection and to assess the effectiveness of interventions to control the coronavirus disease 2019 (COVID-19). A susceptible-exposed-infectious-asymptomatic-recovered (SEIAR) model was developed for the assessment. The information of each confirmed case and asymptomatic infection was collected from Ningbo Center for Disease Control and Prevention (CDC) to calculate the key parameters of the model in Ningbo City, China. A total of 157 confirmed COVID-19 cases (including 51 imported cases and 106 secondary cases) and 30 asymptomatic infections were reported in Ningbo City. The proportion of asymptomatic infections had an increasing trend. The proportion of elder people in the asymptomatic infections was lower than younger people, and the difference was statistically significant (Fisher's Exact Test, P = 0.034). There were 22 clusters associated with 167 SARS-CoV-2 infections, among which 29 cases were asymptomatic infections, accounting for 17.37%. We found that the secondary attack rate (SAR) of asymptomatic infections was almost the same as that of symptomatic cases, and no statistical significance was observed (χ2 = 0.052, P = 0.819) by Kruskal-Wallis test. The effective reproduction number (Reff) was 1.43, which revealed that the transmissibility of SARS-CoV-2 was moderate. If the interventions had not been strengthened, the duration of the outbreak would have lasted about 16 months with a simulated attack rate of 44.15%. The total attack rate (TAR) and duration of the outbreak would increase along with the increasing delay of intervention. SARS-CoV-2 had moderate transmissibility in Ningbo City, China. The proportion of asymptomatic infections had an increase trend. Asymptomatic infections had the same transmissibility as symptomatic infections. The integrated interventions were implemented at different stages during the outbreak, which turned out to be exceedingly effective in China.
Subject(s)
COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/transmission , Infection Control/methods , Adolescent , Adult , Aged , Aged, 80 and over , Asymptomatic Infections/epidemiology , Basic Reproduction Number , Child , Child, Preschool , China/epidemiology , Cities , Female , Humans , Incidence , Infant , Male , Middle Aged , Models, Theoretical , Young AdultABSTRACT
Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.
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Brain Diseases/metabolism , Brain/metabolism , COVID-19/metabolism , Olfactory Bulb/metabolism , SARS-CoV-2/metabolism , Animals , Astrocytes/metabolism , Astrocytes/pathology , Astrocytes/virology , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , COVID-19/pathology , Disease Models, Animal , Humans , Macaca mulatta , Microglia/metabolism , Microglia/pathology , Microglia/virology , Neurons/metabolism , Neurons/pathology , Neurons/virology , Olfactory Bulb/pathology , Olfactory Bulb/virologyABSTRACT
BACKGROUND: Novel coronavirus disease 2019 (COVID-19) causes an immense disease burden. Although public health countermeasures effectively controlled the epidemic in China, non-pharmaceutical interventions can neither be maintained indefinitely nor conveniently implemented globally. Vaccination is mainly used to prevent COVID-19, and most current antiviral treatment evaluations focus on clinical efficacy. Therefore, we conducted population-based simulations to assess antiviral treatment effectiveness among different age groups based on its clinical efficacy. METHODS: We collected COVID-19 data of Wuhan City from published literature and established a database (from 2 December 2019 to 16 March 2020). We developed an age-specific model to evaluate the effectiveness of antiviral treatment in patients with COVID-19. Efficacy was divided into three types: (1) viral activity reduction, reflected as transmission rate decrease [reduction was set as v (0-0.8) to simulate hypothetical antiviral treatments]; (2) reduction in the duration time from symptom onset to patient recovery/removal, reflected as a 1/γ decrease (reduction was set as 1-3 days to simulate hypothetical or real-life antiviral treatments, and the time of asymptomatic was reduced by the same proportion); (3) fatality rate reduction in severely ill patients (fc) [reduction (z) was set as 0.3 to simulate real-life antiviral treatments]. The population was divided into four age groups (groups 1, 2, 3 and 4), which included those aged ≤ 14; 15-44; 45-64; and ≥ 65 years, respectively. Evaluation indices were based on outbreak duration, cumulative number of cases, total attack rate (TAR), peak date, number of peak cases, and case fatality rate (f). RESULTS: Comparing the simulation results of combination and single medication therapy s, all four age groups showed better results with combination medication. When 1/γ = 2 and v = 0.4, age group 2 had the highest TAR reduction rate (98.48%, 56.01-0.85%). When 1/γ = 2, z = 0.3, and v = 0.1, age group 1 had the highest reduction rate of f (83.08%, 0.71-0.12%). CONCLUSIONS: Antiviral treatments are more effective in COVID-19 transmission control than in mortality reduction. Overall, antiviral treatments were more effective in younger age groups, while older age groups showed higher COVID-19 prevalence and mortality. Therefore, physicians should pay more attention to prevention of viral spread and patients deaths when providing antiviral treatments to patients of older age groups.
Subject(s)
Antiviral Agents/therapeutic use , COVID-19/prevention & control , SARS-CoV-2/drug effects , Adolescent , Age Factors , Aged , COVID-19/epidemiology , COVID-19/virology , China/epidemiology , Humans , Infectious Disease Incubation Period , Middle Aged , Models, Statistical , Young AdultABSTRACT
BACKGROUND & AIMS: Gastrointestinal (GI) manifestations have been increasingly reported in patients with coronavirus disease 2019 (COVID-19). However, the roles of the GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We investigated how the GI tract is involved in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19. METHODS: Our previously established nonhuman primate (NHP) model of COVID-19 was modified in this study to test our hypothesis. Rhesus monkeys were infected with an intragastric or intranasal challenge with SARS-CoV-2. Clinical signs were recorded after infection. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction. Host responses to SARS-CoV-2 infection were evaluated by examining inflammatory cytokines, macrophages, histopathology, and mucin barrier integrity. RESULTS: Intranasal inoculation with SARS-CoV-2 led to infections and pathologic changes not only in respiratory tissues but also in digestive tissues. Expectedly, intragastric inoculation with SARS-CoV-2 resulted in the productive infection of digestive tissues and inflammation in both the lung and digestive tissues. Inflammatory cytokines were induced by both types of inoculation with SARS-CoV-2, consistent with the increased expression of CD68. Immunohistochemistry and Alcian blue/periodic acid-Schiff staining showed decreased Ki67, increased cleaved caspase 3, and decreased numbers of mucin-containing goblet cells, suggesting that the inflammation induced by these 2 types of inoculation with SARS-CoV-2 impaired the GI barrier and caused severe infections. CONCLUSIONS: Both intranasal and intragastric inoculation with SARS-CoV-2 caused pneumonia and GI dysfunction in our rhesus monkey model. Inflammatory cytokines are possible connections for the pathogenesis of SARS-CoV-2 between the respiratory and digestive systems.
Subject(s)
COVID-19/transmission , Gastroenteritis/pathology , Gastrointestinal Tract/pathology , Lung/pathology , Animals , Bronchi/metabolism , Bronchi/pathology , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , COVID-19 Nucleic Acid Testing , Caspase 3/metabolism , Cytokines/immunology , Disease Models, Animal , Gastric Mucosa , Gastroenteritis/metabolism , Gastroenteritis/virology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/metabolism , Goblet Cells/pathology , Intestine, Small/metabolism , Intestine, Small/pathology , Ki-67 Antigen/metabolism , Lung/diagnostic imaging , Lung/immunology , Lung/metabolism , Macaca mulatta , Nasal Mucosa , RNA, Viral/isolation & purification , Random Allocation , Rectum/metabolism , Rectum/pathology , SARS-CoV-2 , Trachea/metabolism , Trachea/pathologyABSTRACT
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Teicoplanin/analogs & derivatives , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Caco-2 Cells , Chlorocebus aethiops , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Protein Binding/drug effects , Teicoplanin/pharmacokinetics , Teicoplanin/pharmacology , Vero CellsABSTRACT
Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a pandemic event in the world, it has not only caused huge economic losses, but also a serious threat to global public health. Many scientific questions about SARS-CoV-2 and Coronavirus disease (COVID-19) were raised and urgently need to be answered, including the susceptibility of animals to SARS-CoV-2 infection. Here we tested whether tree shrew, an emerging experimental animal domesticated from wild animal, is susceptible to SARS-CoV-2 infection. No clinical signs were observed in SARS-CoV-2 inoculated tree shrews during this experiment except the increasing body temperature particularly in female animals. Low levels of virus shedding and replication in tissues occurred in all three age groups. Notably, young tree shrews (6 months to 12 months) showed virus shedding at the earlier stage of infection than adult (2 years to 4 years) and old (5 years to 7 years) animals that had longer duration of virus shedding comparatively. Histopathological examine revealed that pulmonary abnormalities were the main changes but mild although slight lesions were also observed in other tissues. In summary, tree shrew is less susceptible to SARS-CoV-2 infection compared with the reported animal models and may not be a suitable animal for COVID-19 related researches. However, tree shrew may be a potential intermediate host of SARS-CoV-2 as an asymptomatic carrier.
Subject(s)
Coronavirus Infections/veterinary , Host Specificity/physiology , Pandemics/veterinary , Pneumonia, Viral/veterinary , Tupaiidae/virology , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/pathology , Disease Susceptibility/veterinary , Disease Susceptibility/virology , Female , Male , Pneumonia, Viral/pathology , SARS-CoV-2 , Viral Load , Virus Shedding/physiologyABSTRACT
BACKGROUND: The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also called 2019-nCoV) causes different morbidity risks to individuals in different age groups. This study attempts to quantify the age-specific transmissibility using a mathematical model. METHODS: An epidemiological model with five compartments (susceptible-exposed-symptomatic-asymptomatic-recovered/removed [SEIAR]) was developed based on observed transmission features. Coronavirus disease 2019 (COVID-19) cases were divided into four age groups: group 1, those ≤ 14 years old; group 2, those 15 to 44 years old; group 3, those 45 to 64 years old; and group 4, those ≥ 65 years old. The model was initially based on cases (including imported cases and secondary cases) collected in Hunan Province from January 5 to February 19, 2020. Another dataset, from Jilin Province, was used to test the model. RESULTS: The age-specific SEIAR model fitted the data well in each age group (P < 0.001). In Hunan Province, the highest transmissibility was from age group 4 to 3 (median: ß43 = 7.71 × 10- 9; SAR43 = 3.86 × 10- 8), followed by group 3 to 4 (median: ß34 = 3.07 × 10- 9; SAR34 = 1.53 × 10- 8), group 2 to 2 (median: ß22 = 1.24 × 10- 9; SAR22 = 6.21 × 10- 9), and group 3 to 1 (median: ß31 = 4.10 × 10- 10; SAR31 = 2.08 × 10- 9). The lowest transmissibility was from age group 3 to 3 (median: ß33 = 1.64 × 10- 19; SAR33 = 8.19 × 10- 19), followed by group 4 to 4 (median: ß44 = 3.66 × 10- 17; SAR44 = 1.83 × 10- 16), group 3 to 2 (median: ß32 = 1.21 × 10- 16; SAR32 = 6.06 × 10- 16), and group 1 to 4 (median: ß14 = 7.20 × 10- 14; SAR14 = 3.60 × 10- 13). In Jilin Province, the highest transmissibility occurred from age group 4 to 4 (median: ß43 = 4.27 × 10- 8; SAR43 = 2.13 × 10- 7), followed by group 3 to 4 (median: ß34 = 1.81 × 10- 8; SAR34 = 9.03 × 10- 8). CONCLUSIONS: SARS-CoV-2 exhibits high transmissibility between middle-aged (45 to 64 years old) and elderly (≥ 65 years old) people. Children (≤ 14 years old) have very low susceptibility to COVID-19. This study will improve our understanding of the transmission feature of SARS-CoV-2 in different age groups and suggest the most prevention measures should be applied to middle-aged and elderly people.
Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Models, Statistical , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Adolescent , Adult , Age Factors , Aged , Betacoronavirus/isolation & purification , COVID-19 , Female , Humans , Male , Middle Aged , Pandemics , SARS-CoV-2 , Young AdultABSTRACT
Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.
Subject(s)
Betacoronavirus/pathogenicity , Callithrix/virology , Coronavirus Infections/epidemiology , Disease Models, Animal , Macaca fascicularis/virology , Macaca mulatta/virology , Pandemics , Pneumonia, Viral/epidemiology , Animals , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , Body Temperature , Body Weight , COVID-19 , Callithrix/immunology , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokines/biosynthesis , Cytokines/classification , Cytokines/immunology , Disease Susceptibility , Female , Humans , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung/virology , Macaca fascicularis/immunology , Macaca mulatta/immunology , Male , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2 , Species Specificity , Tomography, X-Ray Computed , Viral Load , Virus ReplicationABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.