B-cells and antibodies as contributors to effector immune responses in tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is still a major threat to mankind, urgently requiring improved vaccination and therapeutic strategies to reduce TB-disease burden. Most present vaccination strategies mainly aim to induce cell-mediated immunity (CMI), yet a series of independent studies has shown that B-cells and antibodies (Abs) may contribute significantly to reduce the mycobacterial burden. Although early studies using B-cell knock out animals did not support a major role for B-cells, more recent studies have provided new evidence that B-cells and Abs can contribute significantly to host defense against Mtb. B-cells and Abs exist in many different functional subsets, each equipped with unique functional properties. In this review, we will summarize current evidence on the contribution of B-cells and Abs to immunity toward Mtb, their potential utility as biomarkers, and their functional contribution to Mtb control.Immunogenetics and cellular immunology of bacterial infectious disease

Antibody glycosylation in inflammation, disease and vaccination

Immunogenetics and cellular immunology of bacterial infectious disease

The in vivo transcriptomic blueprint of Mycobacterium tuberculosis in the lung

Mycobacterium tuberculosis (Mtb) genes encoding proteins targeted by vaccines and drugs should be expressed in the lung, the main organ affected by Mtb, for these to be effective. However, the pulmonary expression of most Mtb genes and their proteins remains poorly characterized. The aim of this study is to fill this knowledge gap. We analyzed large scale transcriptomic datasets from specimens of Mtb-infected humans, TB-hypersusceptible (C3H/FeJ) and TB-resistant (C57BL/6J) mice and compared data to in vitro cultured Mtb gene-expression profiles. Results revealed high concordance in the most abundantly in vivo expressed genes between pulmonary Mtb transcriptomes from different datasets and different species. As expected, this contrasted with a lower correlation found with the highest expressed Mtb genes from in vitro datasets. Among the most consistently and highly in vivo expressed genes, 35 have not yet been explored as targets for vaccination or treatment. More than half of these genes are involved in protein synthesis or metabolic pathways. This first lung-oriented multi-study analysis of the in vivo expressed Mtb-transcriptome provides essential data that considerably increase our understanding of pulmonary TB infection biology, and identifies novel molecules for target-based TB-vaccine and drug development.Immunogenetics and cellular immunology of bacterial infectious disease

New high-throughput technologies for drug screening in animal models of TB

Animal science

Host-directed therapy to combat mycobacterial infections*

Upon infection, mycobacteria, such as Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria (NTM), are recognized by host innate immune cells, triggering a series of intracellular processes that promote mycobacterial killing. Mycobacteria, however, have developed multiple counter-strategies to persist and survive inside host cells. By manipulating host effector mechanisms, including phagosome maturation, vacuolar escape, autophagy, antigen presentation, and metabolic pathways, pathogenic mycobacteria are able to establish long-lasting infection. Counteracting these mycobacteria-induced host modifying mechanisms can be accomplished by host-directed therapeutic (HDT) strategies. HDTs offer several major advantages compared to conventional antibiotics: (a) HDTs can be effective against both drug-resistant and drug-susceptible bacteria, as well as potentially dormant mycobacteria; (b) HDTs are less likely to induce bacterial drug resistance; and (c) HDTs could synergize with, or shorten antibiotic treatment by targeting different pathways. In this review, we will explore host-pathogen interactions that have been identified for Mtb for which potential HDTs impacting both innate and adaptive immunity are available, and outline those worthy of future research. We will also discuss possibilities to target NTM infection by HDT, although current knowledge regarding host-pathogen interactions for NTM is limited compared to Mtb. Finally, we speculate that combinatorial HDT strategies can potentially synergize to achieve optimal mycobacterial host immune control.Immunogenetics and cellular immunology of bacterial infectious disease

The role of donor-unrestricted T-cells, innate lymphoid cells, and NK cells in anti-mycobacterial immunity

Vaccination strategies against mycobacteria, focusing mostly on classical T- and B-cells, have shown limited success, encouraging the addition of alternative targets. Classically restricted T-cells recognize antigens presented via highly polymorphic HLA class Ia and class II molecules, while donor-unrestricted T-cells (DURTs), with few exceptions, recognize ligands via genetically conserved antigen presentation molecules. Consequently, DURTs can respond to the same ligands across diverse human populations. DURTs can be activated either through cognate TCR ligation or via bystander cytokine signaling. TCR-driven antigen-specific activation of DURTs occurs upon antigen presentation via non-polymorphic molecules such as HLA-E, CD1, MR1, and butyrophilin, leading to the activation of HLA-E-restricted T-cells, CD1-restricted T-cells, mucosal-associated invariant T-cells (MAITs), and TCR gamma delta T-cells, respectively. NK cells and innate lymphoid cells (ILCs), which lack rearranged TCRs, are activated through other receptor-triggering pathways, or can be engaged through bystander cytokines, produced, for example, by activated antigen-specific T-cells or phagocytes. NK cells can also develop trained immune memory and thus could represent cells of interest to mobilize by novel vaccines. In this review, we summarize the latest findings regarding the contributions of DURTs, NK cells, and ILCs in anti-M tuberculosis, M leprae, and non-tuberculous mycobacterial immunity and explore possible ways in which they could be harnessed through vaccines and immunotherapies to improve protection against Mtb.Immunogenetics and cellular immunology of bacterial infectious disease

Potential of Mycobacterium tuberculosis resuscitation-promoting factors as antigens in novel tuberculosis sub-unit vaccines

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Pharmacological poly (ADP-ribose) polymerase inhibitors decrease Mycobacterium tuberculosis survival in human macrophages

Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processes and immune responses to Mycobacterium tuberculosis (Mtb) is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with Mtb infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against Mtb in human macrophage subsets, the predominant target cell of Mtb. Pharmacological inhibition of PARP decreased intracellular Mtb and MDR-Mtb levels in human macrophages, identifying PARP as a potential target for host-directed therapy against Mtb. PARP inhibition was associated with modified chemokine secretion and upregulation of cell surface activation markers by human macrophages. Targeting LDH, a secondary target of the PARP inhibitor rucaparib, resulted in decreased intracellular Mtb, suggesting a metabolic role in rucaparib-induced control of Mtb. We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.Immunogenetics and cellular immunology of bacterial infectious disease

Potential of DosR and Rpf antigens from Mycobacterium tuberculosis to discriminate between latent and active tuberculosis in a tuberculosis endemic population of Medellin Colombia

Immunogenetics and cellular immunology of bacterial infectious disease