ObjectivePatients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD).DesignCharacterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity.ResultsA group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats.ConclusionAberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients.Trial registration numberThis study was registered at ClinicalTrials.gov (NCT03010696).

Tuberculosis (TB) is an international public health priority and kills almost two million people annually. TB is out of control in Africa due to increasing poverty and HIV coinfection, and drug-resistant TB threatens to destabilize TB control efforts in several regions of the world. Existing diagnostic tools and therapeutic interventions for TB are suboptimal. Thus, new vaccines, immunotherapeutic interventions and diagnostic tools are urgently required to facilitate TB control efforts. An improved understanding of the immunopathogenesis of TB can facilitate the identification of correlates of immune protection, the design of effective vaccines, the rational selection of immunotherapeutic agents, the evaluation of new drug candidates, and drive the development of new immunodiagnostic tools. Here we review the immunology of TB with a focus on aspects that are clinically and therapeutically relevant. An immunologically orientated approach to tackling TB can only succeed with concurrent efforts to alleviate poverty and reduce the global burden of HIV.

Tuberculosis (TB) kills more individuals in the world than any other disease, and a threat made direr by the coverage of drug-resistant strains of Mycobacterium tuberculosis (Mtb). Bacillus Calmette–Guérin (BCG) is the single TB vaccine licensed for use in human beings and effectively protects infants and children against severe military and meningeal TB. We applied advanced computational techniques to develop a universal TB vaccine. In the current study, we select the very conserved, experimentally confirmed Mtb antigens, including Rv2608, Rv2684, Rv3804c (Ag85A), and Rv0125 (Mtb32A) to design a novel multi-epitope subunit vaccine. By using the Immune Epitopes Database (IEDB), we predicted different B-cell and T-cell epitopes. An adjuvant (Griselimycin) was also added to vaccine construct to improve its immunogenicity. Bioinformatics tools were used to predict, refined, and validate the 3D structure and then docked with toll-like-receptor (TLR-3) using different servers. The constructed vaccine was used for further processing based on allergenicity, antigenicity, solubility, different physiochemical properties, and molecular docking scores. The in silico immune simulation results showed significant response for immune cells. For successful expression of the vaccine in E. coli, in-silico cloning and codon optimization were performed. This research also sets out a good signal for the design of a peptide-based tuberculosis vaccine. In conclusion, our findings show that the known multi-epitope vaccine may activate humoral and cellular immune responses and maybe a possible tuberculosis vaccine candidate. Therefore, more experimental validations should be exposed to it.

Tuberculosis (TB) is a serious disease around the world. Bacillus Calmette-Guérin (BCG) is the only TB vaccine licensed for use in human beings, and is effective in protecting infants and children against severe miliary and meningeal TB. However, BCG's protective efficacy is variable in adults. Novel TB vaccine candidates being developed include whole-cell vaccines (recombinant BCG (rBCG), attenuated Mycobacterium tuberculosis, killed M. tuberculosis or Mycobacterium vaccae), adjuvanted protein subunit vaccines, viral vector-delivered subunit vaccines, plasmid DNA vaccines, RNA-based vaccines etc. At least 12 novel TB vaccine candidates are now in clinical trials, including killed M. vaccae, rBCG ΔureC::hly, adjuvanted fusion proteins M72 and H56 and viral vectored MVA85A. Unfortunately, in TB, there are no correlates of vaccine-induced protection, although cell-mediated immune responses such as interferon-gamma (IFN-γ) production are widely used to assess vaccine's immunogenicity. Recent studies suggested that central memory T cells and local secreted IgA correlated with protection against TB disease. Clinical TB vaccine efficacy trials should invest in identifying correlates of protection, and evaluate new TB biomarkers emerging from human and animal studies. Accumulating new knowledge on M. tuberculosis antigens and immune profiles correlating with protection or disease risk will be of great help in designing next generation of TB vaccines.

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