Project description:The emergence and fast global spread of COVID-19 has presented one of the greatest public health challenges in modern times with no proven cure or vaccine. Africa is still early in this epidemic, therefore the extent of disease severity is not yet clear. We used a mathematical model to fit to the observed cases of COVID-19 in South Africa to estimate the basic reproductive number and critical vaccination coverage to control the disease for different hypothetical vaccine efficacy scenarios. We also estimated the percentage reduction in effective contacts due to the social distancing measures implemented. Early model estimates show that COVID-19 outbreak in South Africa had a basic reproductive number of 2.95 (95% credible interval [CrI] 2.83–3.33). A vaccine with 70% efficacy had the capacity to contain COVID-19 outbreak but at very higher vaccination coverage 94.44% (95% Crl 92.44–99.92%) with a vaccine of 100% efficacy requiring 66.10% (95% Crl 64.72–69.95%) coverage. Social distancing measures put in place have so far reduced the number of social contacts by 80.31% (95% Crl 79.76–80.85%). These findings suggest that a highly efficacious vaccine would have been required to contain COVID-19 in South Africa. Therefore, the current social distancing measures to reduce contacts will remain key in controlling the infection in the absence of vaccines and other therapeutics.
Project description:The rapid development of safe and effective treatments for COVID-19 had become a top priority to fight against this spreading pandemic worldwide in 2019. 20%–30% of COVID-19 patients experience severe cardiovascular damage, patients with pre-existing heart complications are more likely to develop severe illness and have higher risk of death compared with patients without co-morbidities. In such a context, whether the repurposed drugs are at risk of inducing heart damage to COVID-19 patients remains unclear. Here, we demonstrated that four antiviral drugs, including apilimod, remdesivir, ritonavir, and lopinavir, exhibit cardiotoxicity at clinically relevant doses. RNA-seq analysis revealed that human pluripotent stem cell-derived cardiomyocytes (hCMs) treated by each drug had significantly different expression profiles when compared with the untreated control. The expression of genes that regulate cardiomyocyte function, such as sarcomere organization and ion hemostasis, was significantly altered after drug treatment. These results not only warrant caution and careful monitoring when prescribing the above-mentioned drugs in patients, but also provide a valuable platform for understanding the molecular mechanism underlined the toxic effects of these prospective drugs and for protective agent discovery.
Project description:Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar dysfunction shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of fatal COVID-19.
Project description:The causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical manifestations in disease-ridden patients. Differences in the severity of COVID-19 ranges from asymptomatic infections and mild cases to the severe form, leading to acute respiratory distress syndrome (ARDS) and multiorgan failure with poor survival. MiRNAs can regulate various cellular processes, including proliferation, apoptosis, and differentiation, by binding to the 3′UTR of target mRNAs inducing their degradation, thus serving a fundamental role in post-transcriptional repression. Alterations of miRNA levels in the blood have been described in multiple inflammatory and infectious diseases, including SARS-related coronaviruses. We used microarrays to delineate the miRNAs and snoRNAs signature in the peripheral blood of severe COVID-19 cases (n=9), as compared to mild (n=10) and asymptomatic (n=10) patients, and identified differentially expressed transcripts in severe versus asymptomatic, and others in severe versus mild COVID-19 cases. A cohort of 29 male age-matched patients were selected. All patients were previously diagnosed with COVID-19 using TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, Massachusetts), or Cobas SARS-CoV-2 Test (Roche Diagnostics, Rotkreuz, Switzerland), with a CT value < 30. Additional criterion for selection was age between 35 and 75 years. Participants were grouped into severe, mild and asymptomatic. Classifying severe cases was based on requirement of high-flow oxygen support and ICU admission (n=9). Whereas mild patients were identified based on symptoms and positive radiographic findings with pulmonary involvement (n=10). Patients with no clinical presentation were labelled as asymptomatic cases (n=10).
Project description:Red blood cells (RBC) depleted whole blood from COVID-19 patients and controls was harvested and processed in order to performed 10X single cell RNA-seq. For COVID-19 patients 2 samples 10 days a part were analyzed.
Project description:Background - The coronavirus disease 2019 (COVID-19) is rapidly spreading in China and more than 30 countries over last two months. COVID-19 has multiple characteristics distinct from other infectious diseases, including high infectivity during incubation, time delay between real dynamics and daily observed number of confirmed cases, and the intervention effects of implemented quarantine and control measures. Methods - We develop a Susceptible, Un-quanrantined infected, Quarantined infected, Confirmed infected (SUQC) model to characterize the dynamics of COVID-19 and explicitly parameterize the intervention effects of control measures, which is more suitable for analysis than other existing epidemic models. Results - The SUQC model is applied to the daily released data of the confirmed infections to analyze the outbreak of COVID-19 in Wuhan, Hubei (excluding Wuhan), China (excluding Hubei) and four first-tier cities of China. We found that, before January 30, 2020, all these regions except Beijing had a reproductive number R &gt; 1, and after January 30, all regions had a reproductive number R lesser than 1, indicating that the quarantine and control measures are effective in preventing the spread of COVID-19. The confirmation rate of Wuhan estimated by our model is 0.0643, substantially lower than that of Hubei excluding Wuhan (0.1914), and that of China excluding Hubei (0.2189), but it jumps to 0.3229 after February 12 when clinical evidence was adopted in new diagnosis guidelines. The number of unquarantined infected cases in Wuhan on February 12, 2020 is estimated to be 3,509 and declines to 334 on February 21, 2020. After fitting the model with data as of February 21, 2020, we predict that the end time of COVID-19 in Wuhan and Hubei is around late March, around mid March for China excluding Hubei, and before early March 2020 for the four tier-one cities. A total of 80,511 individuals are estimated to be infected in China, among which 49,510 are from Wuhan, 17,679 from Hubei (excluding Wuhan), and the rest 13,322 from other regions of China (excluding Hubei). Note that the estimates are from a deterministic ODE model and should be interpreted with some uncertainty. Conclusions - We suggest that rigorous quarantine and control measures should be kept before early March in Beijing, Shanghai, Guangzhou and Shenzhen, and before late March in Hubei. The model can also be useful to predict the trend of epidemic and provide quantitative guide for other countries at high risk of outbreak, such as South Korea, Japan, Italy and Iran.
Project description:To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immune-related factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. To further exploring the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases.
Project description:Fire disturbances are becoming more common, more intense, and further-reaching across the globe, with consequences for ecosystem functioning. Importantly, fire can have strong effects on the soil microbiome, including community and functional changes after fire, but surprisingly little is known regarding the role of soil fire legacy in shaping responses to recent fire. To address this gap, we conducted a manipulative field experiment administering fire across 32 soils with varying fire legacies, including combinations of 1-7 historic fires and 1-33 years since most recent fire. We analyzed soil metatranscriptomes, determining for the first time how fire and fire legacy interactively affect metabolically-active soil taxa, the microbial regulation of important carbon (C), nitrogen (N) and phosphorus (P) cycling, expression of carbohydrate-cycling enzyme pathways, and functional gene co-expression networks. Experimental fire strongly downregulated fungal activity while upregulating many bacterial and archaeal phyla. Further, fire decreased soil capacity for microbial C and N cycling and P transport, and drastically rewired functional gene co-expression. Perhaps most importantly, we highlight a novel role of soil fire legacy in regulation of microbial C, N, and P responses to recent fire. We observed a greater number of functional genes responsive to the interactive effects of fire and fire legacy than those affected solely by recent fire, indicating that many functional genes respond to fire only under certain fire legacy contexts. Therefore, without incorporating fire legacy of soils, studies will miss important ways that fire shapes microbial roles in ecosystem functioning. Finally, we showed that fire caused significant downregulation of carbon metabolism and nutrient cycling genes in microbiomes under abnormal soil fire histories, producing a novel warning for the future: human manipulation of fire legacies, either indirectly through global change-induced fire intensification or directly through fire suppression, can negatively impact soil microbiome functional responses to new fires.