Rare Variants in Inborn Errors of Immunity Genes Associated with Covid-19 Severity

Covid-19 is a contagious disease caused by SARS-CoV-2, a novel severe acute respiratory syndrome coronavirus. Common variants and networks underlying host genetic mechanisms have been extensively studied to identify disease-associated genetic factors. However, there are few studies about the rare variants, typically inborn errors of immunity, in understanding the host genetics behind Covid-19 infection, especially in the Chinese population. To fill this gap, we investigate likely-deleterious missense and high-confidence predicted loss-of-function variants by (a) performing gene- and pathway-level association analyses, (b) examining known genes involved in type I interferon signaling and others previously reported in Covid-19 disease, and (c) identifying candidate genes with accumulating mutations and their potential protein-protein interactions with known genes. Based on our analyses, several putative genes and pathways are uncovered and worth further investigation, for example, genes IL12RB1, TBK1, and TLR3, and pathways Tuberculosis (hsa:05152), Primary Immunodeficiency (hsa:05340), and Influenza A (hsa:05164). These regions generally play an essential role in regulating antiviral innate immunity responses to foreign pathogens and in responding to many inflammatory diseases. We believe that to some extent, as an acute inflammatory disease, Covid-19 is also affected by these inborn errors of immunity. We hope that the identification of these rare genetic factors will provide new insights into the genetic architecture of Covid-19.

Plasma cell-free DNA promise disease monitoring and tissue injury assessment of COVID-19

COVID-19 is a huge threat to global health. Due to the lack of definitive etiological therapeutics currently, effective disease monitoring is of high clinical value for better healthcare and management of the large number of COVID-19 patients. In this study, we recruited 37 COVID-19 patients, collected 176 blood samples upon diagnosis and during treatment, and analyzed cell-free DNA (cfDNA) in these samples. We report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA characteristics reflect patient-specific physiological conditions during treatment. Further analysis on tissue origin tracing of cfDNA reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, we demonstrate the translational merit of cfDNA as valuable analyte for effective disease monitoring, as well as tissue injury assessment in COVID-19 patients.

A Chinese host genetic study discovered type I interferons and causality of cholesterol levels and WBC counts on COVID-19 severity

As of early May 2021, the ongoing pandemic COVID-19 has caused over 160 million of infections and over 3 million deaths worldwide. Many risk factors, such as age, gender, and comorbidities, have been studied to explain the variable symptoms of infected patients. However, these effects may not fully account for the diversity in disease severity. Here, we present a comprehensive analysis of a broad range of patients laboratory and clinical assessments to investigate the genetic contributions to COVID-19 severity. By performing GWAS analysis, we discovered several concrete associations for laboratory features. Based on these findings, we performed Mendelian randomization (MR) analysis to investigate the causality of laboratory traits on disease severity. From the MR study, we identified two causal traits, cholesterol levels and WBC counts. The functional gene related to cholesterol levels is ApoE and people with particular ApoE genotype are more likely to have higher cholesterol levels, facilitating the process that SARS-CoV-2 binds on its receptor ACE2 and aggravating COVID-19 disease. The functional gene related to WBC counts is MHC system that plays a central role in the immune system. The host immune response to the SARS-CoV-2 infection greatly affects the patients severity status and clinical outcome. Additionally, our gene-based and GSEA analysis revealed interferon pathways, including type I interferon receptor binding, regulation of IFNA signaling, and SARS coronavirus and innate immunity. We hope that our work will make a contribution in studying the genetic mechanisms of disease illness and serve as useful reference for the clinical diagnosis and treatment of COVID-19.

Clinical characteristics of Covid-19 patients with re-positive test results: an observational study

BackgroundWith coronavirus disease 2019 (Covid-19) ravaging the global, concern has been aroused whether discharged Covid-19 patients with reappeared positive nucleic acid test results are infected again. ObjectiveTo analyze the clinical characteristics of discharged Covid-19 patients with reappeared positive nucleic acid test results and to track clinical outcomes of them. MethodsWe extracted clinical data on 938 Covid-19 patients from Wuhan Union Hospital (West Branch), and we obtained information about residual symptoms and nucleic acid tests after discharge through follow-up study. We evaluated the relationship of clinical characteristics and reappeared positive results. Each patient had at least 44 days of follow-up. ResultsOf 938 discharged patients, a total of 58 (6.2%) had reappeared positive nucleic acid test results and 880 remain negative. Among patients over the age of 50, the factors we found to be associated with re-positive results were coronary artery disease (14.1%, vs. 5.5% among those without coronary artery disease; odds ratio, 2.81; 95% confidence interval [CI], 1.28 to 6.15), and hypertension (9.5%, vs. 4.9% among those without hypertension; odds ratio, 2.05; 95% CI, 1.10 to 3.82). As of May 11, 2020, 54 (93.1%) re-positive patients turned negative again while two patients remained positive, and two patients was lost to the second follow-up. ConclusionCoexisting diseases including coronary artery disease and hypertension were substantial risk factors for re-positive outcomes among patients over 50. And most re-positive patients tended to return negative eventually.

Insights on the peacetime-wartime combination mechanism for general hospitals in the face of emerging infectious diseases / 中华医院管理杂志

General hospitals play an important role in the prevention and control of emerging infectious diseases, making it imperative to stand by for outbreaks of epidemics in peacetime. This study analyzed the necessity of the mechanism of adapting these hospitals to both peacetime and wartime against emerging infectious diseases. In addition, the authors identified existing problems in dealing with emerging infectious diseases, and put forward corresponding suggestions: readiness in the conversion into epidemic-control; strengthened comprehensive prevention and control of nosocomial infection; strengthened construction of epidemic prevention teambuilding; an emergency material supply guarantee mechanism; an optimized monitoring and early warning mechanism; enhanced risk management and joint prevention and control.

Competing endogenous RNA and tumor pathological mechanism / 国际肿瘤学杂志

Competing endogenous RNA (ceRNA) is a class of RNA which includes mRNA,pseudogenes,long non-coding RNA (lncRNA),circular RNA (circRNA).ceRNA weakens its inhibitory effect on mRNA translation through competitive binding with shared microRNA (miRNA).Many studies have confirmed that the disorder of ceRNA is closely related to the occur-ence of breast cancer,gastric cancer,lymphoma and other tumors.With the improvement of researches,ceRNA may be used as a tumor marker of clinical diagnosis and therapeutic target.

Changes of bone marrow microenvironment of myelodysplastic syndromes / 国际肿瘤学杂志

Bone marrow microenvironment is a complex network consisting of hematopoietic stem/pro-genitor cells (HSPCs),non-hematopoietic cells,extracellular matrix and various cytokines.Its components interact to support normal hematopoiesis.Emerging evidence indicates that the dysfunction of mesenchymal stem cells,myeloid-derived suppressor cells,cytokines and the epigenetic alterations of HSPCs in the bone marrow microenvironment could influence normal hematopoiesis.Abnormal hematopoiesis contributes to the occurrence of hematological malignancies,such as myelodysplastic syndromes (MDS).Animal models have confirmed that bone marrow microenvironment plays an important role in the original generation and maintenance of malignant diseases of hematopoietic system.

Promoting the proliferation of bone marrow mesenchymal stem cell by recombinant human granulocyte colony-stimulating factor / 中华器官移植杂志

Objective To investigate the effects on proliferation of bone marrow mesenchymal stem cells (MSCs) by recombinant human granulocyte colony-stimulating factor in mice. Methods Kunming mice were randomly divided into G-CSF and control groups (n=15). The mice were subjected to subcutaneous injections of rhG-CSF at a dose of 80 ?g/kg per day and control of saline for 5 days. The bone marrow was obtained on 6th, 12th and 168th h respectively after the final administration. The MSCs were separated and cultured, and the colony-forming unit-fibroblast (CFU-F) was evaluated. The cell cycle and the surface antigens were analyzed by flow cytometry. Results The number of CFU-F was increased after administration of the rhG-CSF (P 0.05). Flow cytometic detection of MSCs surface marks in fibroblast colony showed CD34~ -, CD133~ -, CD90~ + and CD105~ +, with the percentage of 2.5 %, 3.1 %, 67.0 % and 78.0 %, respectively. After mobilization with rhG-CSF, the percentage of G_0/G_1 phases in bone marrow MNCs was decreased (P

Induced differentiation of human cord blood mesenchymal stem/progenitor cells into cardiomyocyte-like cells in vitro / 华中科技大学学报（医学）（英德文版）

The feasibility of using cord blood mesenchymal stem/progenitor cells (CB-MSPCs) to regenerate cardiomyocytes and the optimal inducing conditions were investigated. The CB mononuclear cells were cultured in low serum DMEM medium to produce an adherent layer. After expansion, the adherent cells were added into cardiomyocyte inducing medium supplemented with 5-azacytidine. Cardiogenic specific contractile protein troponin T staining was performed to identify the cardiomyocyte-like cells. The results showed that the frequency of CB-MSPCs clones in CB mononuclear cells was 0.5 x 10(-6) and about 1.3 x 10(7)-fold expansion was achieved within 20 sub-cultivation. After cardiogenic induction, 70% CB-MSPCs was differentiated into cardiomyocyte-like cells. It was indicated that low serum culture could expand CB-MSPCs extensively and the expanded CB-MSPCs could be induced to differentiate into cardiomyocyte-like cells in high efficiency.

Induced differentiation of human cord blood mesenchymal stem/progenitor cells into cardiomyocyte-like cells in vitro / 华中科技大学学报（医学）（英德文版）

The feasibility of using cord blood mesenchymal stem/progenitor cells (CB-MSPCs) to regenerate cardiomyocytes and the optimal inducing conditions were investigated. The CB mononuclear cells were cultured in low serum DMEM medium to produce an adherent layer. After expansion, the adherent cells were added into cardiomyocyte inducing medium supplemented with 5-azacytidine. Cardiogenic specific contractile protein troponin T staining was performed to identify the cardiomyocyte-like cells. The results showed that the frequency of CB-MSPCs clones in CB mononuclear cells was 0.5 x 10(-6) and about 1.3 x 10(7)-fold expansion was achieved within 20 sub-cultivation. After cardiogenic induction, 70% CB-MSPCs was differentiated into cardiomyocyte-like cells. It was indicated that low serum culture could expand CB-MSPCs extensively and the expanded CB-MSPCs could be induced to differentiate into cardiomyocyte-like cells in high efficiency.