CD4+ Effective Memory T Cell Markers GBP2 and LAG3 Are Risk Factors for PTB and COVID-19 Infection: A Study Integrating Single-Cell Expression Quantitative Trait Locus and Mendelian Randomization Analyses.

Observational studies indicate that variations in peripheral blood mononuclear cell (PBMC) subsets are associated with an increased risk of pulmonary tuberculosis (PTB) and coronavirus disease 2019 (COVID-19), but causal validation is lacking. Here, we combined single-cell expression quantitative trait locus (sc-eQTL) and two-sample mendelian randomization (MR) analyses to elucidate the causal relationship between PBMC subsets and the occurrence of PTB and COVID-19 and verified by RT-qPCR. We observed an increase in the CD4+ Effective Memory T Cell (CD4+ TEM) cluster in both PTB and COVID-19 patients according to the single-cell transcriptional landscape of PBMC. Through MR analysis using an inverse variance weighted (IVW) method, we found strong evidence of positive correlations between CD4+ TEM cell markers (GBP2, TRAV1-2, and ODF2L) and PTB, and between markers (LAG3 and SLFN5) and COVID-19, especially highlighted by lead eQTL-SNPs of GBP2 (rs2256752, p = 4.76321 × 10-15) and LAG3 (rs67706382, p = 6.16× 10-16). Similar results were observed in validation sets, and no pleiotropy was detected in sensitivity analyses including weighted median (WM), MR-Egger, MR-pleiotropy residual sum and outlier, and leave-one-out analyses (all p > 0.05). We visualized the colocalization of marker-eQTLs and markers of PTB and COVID-19 genome-wide association study (GWAS) associations. Based on CellChat analyses, monocytes communicated predominantly with CD4+ TEM cells positively expressing PTB markers (GBP2, TRAV1-2, and ODF2L) and COVID-19 markers (LAG3 and SLFN5) in both PTB and COVID-19. Our data suggest a causal effect between two key CD4+ TEM cell markers (GBP2 and LAG3) and the risk for PTB and COVID-19 infection. Our findings provide novel insights into the biological mechanism for PTB and COVID-19 infection, but future single-cell studies are necessary to further enhance understanding of this find.

Cellular and Molecular Network Characteristics of TARM1-Related Genes in Mycobacterium tuberculosis Infections.

Tuberculosis (TB) is a global infectious threat, and the emergence of multidrug-resistant TB has become a major challenge in eradicating the disease that requires the discovery of new treatment strategies. This study aimed to elucidate the immune infiltration and molecular regulatory network of T cell-interacting activating receptors on myeloid cell 1 (TARM1)-related genes based on a bioinformatics analysis. The GSE114911 dataset was obtained from the Gene Expression Omnibus (GEO) and screened to identify 17 TARM1-related differentially expressed genes (TRDEGs). Genes interacting with the TRDEGs were analyzed using a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A gene set enrichment analysis (GSEA) was used to identify the biological pathways significantly associated with a Mycobacterium tuberculosis (Mtb) infection. The key genes were obtained based on Cytoscape's cytoHubba plug-in. Furthermore, protein-protein interaction (PPI) networks were analyzed through STRING, while mRNA-RNA-binding protein (RBP) and mRNA-transcription factor (TF) interaction networks were developed utilizing the StarBase v3.0 and ChIPBase databases. In addition, the diagnostic significance of key genes was evaluated via receiver operating characteristic (ROC) curves, and the immune infiltration was analyzed using an ssGSEA and MCPCounter. The key genes identified in the GSE114911 dataset were confirmed in an independent GSE139825 dataset. A total of seventeen TRDEGs and eight key genes were obtained in a differential expression analysis using the cytoHubba plug-in. Through the GO and KEGG analysis, it was found that these were involved in the NF-κB, PI3K/Akt, MAPK, and other pathways related to inflammation and energy metabolism. Furthermore, the ssGSEA and MCPCounter analysis revealed a significant rise in activated T cells and T helper cells within the Mtb infection group, which were markedly associated with these key genes. This implies their potential significance in the anti-Mtb response. In summary, our results show that TRDEGs are linked to inflammation, energy metabolism, and immune cells, offering fresh insights into the mechanisms underlying TB pathogenesis and supporting further investigation into the possible molecular roles of TARM1 in TB, as well as assisting in the identification of prospective diagnostic biomarkers.

Efficacy and safety of antibiotics for treatment of leptospirosis: a systematic review and network meta-analysis.

BACKGROUND: Leptospirosis, an important zoonotic bacterial disease, commonly affects resource-poor populations and results in significant morbidity and mortality worldwide. The value of antibiotics in leptospirosis remains unclear, as evidenced by the conflicting opinions published. METHODS: We conducted a search in the PubMed, Web of Science, and Cochrane Library databases for studies. These studies included clinical trials and retrospective studies that evaluated the efficacy or safety of antibiotics for leptospirosis treatment. The primary outcomes assessed were defervescence time, mortality rate, and hospital stays. Subgroup analyses were performed based on whether there were cases involving children and whether there were cases of severe jaundice. Safety was defined as the prevalence of adverse events associated with the use of antibiotics. p scores were utilized to rank the efficacy of the antibiotics. RESULTS: There are included 9 randomized controlled trials (RCTs), 1 control trial (CT), and 3 retrospective studies (RS) involving 920 patients and 8 antibiotics. Six antibiotics resulted in significantly shorter defervescence times compared to the control, namely cefotaxime (MD, - 1.88; 95% CI = - 2.60 to - 1.15), azithromycin (MD, - 1.74; 95% CI = - 2.52 to - 0.95), doxycycline (MD, - 1.53; 95% CI = - 2.05 to - 1.00), ceftriaxone (MD, - 1.22; 95% CI = - 1.89 to - 0.55), penicillin (MD, - 1.22; 95% CI = - 1.80 to - 0.64), and penicillin or ampicillin (MD, - 0.08; 95% CI = - 1.01 to - 0.59). The antibiotics were not effective in reducing the mortality and hospital stays. Common adverse reactions to antibiotics included Jarisch-Herxheimer reaction, rash, headache, and digestive reactions (nausea, vomiting, diarrhea, abdominal pain, and others). CONCLUSIONS: Findings recommend that leptospirosis patients be treated with antibiotics, which significantly reduced the leptospirosis defervescence time. Cephalosporins, doxycycline, and penicillin are suggested, and azithromycin may be a suitable alternative for drug-resistant cases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022354938.

The intricate role of CCL5/CCR5 axis in Alzheimer disease.

The morbidity and mortality associated with Alzheimer disease (AD), one of the most common neurodegenerative diseases, are increasing each year. Although both amyloid ß and tau proteins are known to be involved in AD pathology, their detailed functions in the pathogenesis of the disease are not fully understood. There is increasing evidence that neuroinflammation contributes to the development and progression of AD, with astrocytes, microglia, and the cytokines and chemokines they secrete acting coordinately in these processes. Signaling involving chemokine (C-C motif) ligand 5 (CCL5) and its main receptor C-C chemokine receptor 5 (CCR5) plays an important role in normal physiologic processes as well as pathologic conditions such as neurodegeneration. In recent years, many studies have shown that the CCL5/CCR5 axis plays a major effect in the pathogenesis of AD, but there are also a few studies that contradict this. In short, the role of CCL5/CCR5 axis in the pathogenesis of AD is still intricate. This review summarizes the structure, distribution, physiologic functions of the CCL5/CCR5 axis, and the progress in understanding its involvement in the pathogenesis of AD.

Seventy years of evidence on the efficacy and safety of drugs for treating leprosy: a network meta-analysis.

OBJECTIVE: The World Health Organization (WHO) recommends multidrug therapy (MDT) with rifampicin, dapsone, and clofazimine for treating leprosy, which is based on very low-quality evidence. Here, we performed a network meta-analysis (NMA) to produce quantitative evidence to strengthen current WHO recommendations. METHOD: All studies were obtained from Embase and PubMed from the date of establishment to October 9, 2021. Data were synthesized with frequentist random-effects network meta-analyses. Outcomes were assessed using odds ratios (ORs), 95% confidence intervals (95% CIs), and P score. RESULTS: Sixty controlled clinical trials and 9256 patients were included. MDT was effective (range of OR: 1.06-1255584.25) for treating leprosy and multibacillary leprosy. Six treatments (Range of OR: 1.199-4.50) were more effective than MDT. Clofazimine (P score=0.9141) and dapsone+rifampicin (P score=0.8785) were effective for treating type 2 leprosy reaction. There were no significant differences in the safety of any of the tested drug regimens. CONCLUSIONS: The WHO MDT is effective for treating leprosy and multibacillary leprosy, but it may not be effective enough. Pefloxacin and ofloxacin may be good adjunct drugs for increasing MDT efficacy. Clofazimine and dapsone+rifampicin can be used in the treatment of a type 2 leprosy reaction. Single-drug regimens are not efficient enough to treat leprosy, multibacillary leprosy, or a type 2 leprosy reaction. AVAILABILITY OF DATA AND MATERIALS: All data generated or analyzed during this study are included in this published article [and its supplementary information files].

BCG-induced trained immunity: history, mechanisms and potential applications.

The Bacillus Calmette-Guérin (BCG) vaccine was discovered a century ago and has since been clinically applicable. BCG can not only be used for the prevention of tuberculosis, but also has a non-specific protective effect on the human body called trained immunity that is mediated by innate immune cells such as monocytes, macrophages, and natural killer cells. Mechanisms of trained immunity include epigenetic reprogramming, metabolic reprogramming, and long-term protection mediated by hematopoietic stem cells. Trained immunity has so far shown beneficial effects on cancer, viral-infections, autoimmune diseases, and a variety of other diseases, especially bladder cancer, respiratory viruses, and type 1 diabetes. The modulation of the immune response by BCG has led to the development of a variety of recombinant vaccines. Although the specific mechanism of BCG prevention on diseases has not been fully clarified, the potential role of BCG deserves further exploration, which is of great significance for prevention and treatment of diseases.

Lung Organoids as Model to Study SARS-CoV-2 Infection.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has severely affected socio-economic conditions and people's life. The lung is the major target organ infected and (seriously) damaged by SARS-CoV-2, so a comprehensive understanding of the virus and the mechanism of infection are the first choices to overcome COVID-19. Recent studies have demonstrated the enormous value of human organoids as platforms for virological research, making them an ideal tool for researching host-pathogen interactions. In this study, the various existing lung organoids and their identification biomarkers and applications are summarized. At the same time, the seven coronaviruses currently capable of infecting humans are outlined. Finally, a detailed summary of existing studies on SARS-CoV-2 using lung organoids is provided and includes pathogenesis, drug development, and precision treatment. This review highlights the value of lung organoids in studying SARS-CoV-2 infection, bringing hope that research will alleviate COVID-19-associated lung infections.