The pulmonary microbial community, described only a few years ago, forms a discreet part of the human host microbiota. The airway microbiota has been found to be substantially altered in the context ...of numerous respiratory disorders; nonetheless, its role in health and disease is as yet only poorly understood. Another important parameter to consider is the gut–lung axis, where distal (gut) immune modulation during respiratory disease is mediated by the gut microbiota. The use of specific microbiota strains, termed “probiotics,” with beneficial effects on the host immunity and/or against pathogens, has proven successful in the treatment of intestinal disorders and is also showing promise in the context of airway diseases. In this review, we highlight the beneficial role of the body's commensal bacteria during airway infectious diseases, including recent evidence highlighting their local (lung) or distal (gut) contribution in this process.
Mycobacteria, metals, and the macrophage Neyrolles, Olivier; Wolschendorf, Frank; Mitra, Avishek ...
Immunological reviews,
March 2015, Letnik:
264, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Summary
Mycobacterium tuberculosis is a facultative intracellular pathogen that thrives inside host macrophages. A key trait of M. tuberculosis is to exploit and manipulate metal cation trafficking ...inside infected macrophages to ensure survival and replication inside the phagosome. Here, we describe the recent fascinating discoveries that the mammalian immune system responds to infections with M. tuberculosis by overloading the phagosome with copper and zinc, two metals which are essential nutrients in small quantities but are toxic in excess. M. tuberculosis has developed multi‐faceted resistance mechanisms to protect itself from metal toxicity including control of uptake, sequestration inside the cell, oxidation, and efflux. The host response to infections combines this metal poisoning strategy with nutritional immunity mechanisms that deprive M. tuberculosis from metals such as iron and manganese to prevent bacterial replication. Both immune mechanisms rely on the translocation of metal transporter proteins to the phagosomal membrane during the maturation process of the phagosome. This review summarizes these recent findings and discusses how metal‐targeted approaches might complement existing TB chemotherapeutic regimens with novel anti‐infective therapies.
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipid-laden foamy macrophages that are a primary source of ...tissue destruction in patients with TB. In this issue of the JCI, Bedard et al. demonstrate that 1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis, caused lysosomal dysfunction associated with lipid storage in the phagolysosome of macrophages in a manner that mimicked lysosomal storage diseases. This work sheds light on how M. tuberculosis manipulates host lipid metabolism for its survival and opens avenues toward host-directed therapy against TB.
Tuberculosis (TB), caused by the airborne bacterial pathogen
, remains a major source of morbidity and mortality worldwide. So far, the study of host-pathogen interactions in TB has mostly focused on ...the physiology and virulence of the pathogen, as well as, on the various innate and adaptive immune compartments of the host. Microbial organisms endogenous to our body, the so-called microbiota, interact not only with invading pathogens, but also with our immune system. Yet, the impact of the microbiota on host defense against
remains poorly understood. In order to address this question, we adapted a robust and reproducible mouse model of microbial dysbiosis based on a combination of wide-spectrum antibiotics. We found that microbiota dysbiosis resulted in an increased early colonization of the lungs by
during the first week of infection, correlating with an altered diversity of the gut microbiota during this time period. At the cellular level, no significant difference in the recruitment of conventional myeloid cells, including macrophages, dendritic cells and neutrophils, to the lungs could be detected during the first week of infection between microbiota-competent and -deficient mice. At the molecular level, microbiota depletion did not impact the global production of pro-inflammatory cytokines, such as interferon (IFN)γ, tumor necrosis factor (TNF)α and interleukin (IL)-1β in the lungs. Strikingly, a reduced number of mucosal-associated invariant T (MAIT) cells, a population of innate-like lymphocytes whose development is known to depend on the host microbiota, was observed in the lungs of the antibiotics-treated animals after 1week of infection. These cells produced less IL-17A in antibiotics-treated mice. Notably, dysbiosis correction through the inoculation of a complex microbiota in antibiotics-treated animals reversed these phenotypes and improved the ability of MAIT cells to proliferate. Altogether, our results demonstrate that the host microbiota contributes to early protection of lung colonization by
, possibly through sustaining the function(s) of MAIT cells. Our study calls for a better understanding of the impact of the microbiota on host-pathogen interactions in TB. Ultimately, this study may help to develop novel therapeutic approaches based on the use of beneficial microbes, or components thereof, to boost anti-mycobacterial immunity.
The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a ...possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development. To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our "failed" trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models. However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.
The mechanism of latent tuberculosis (TB) infection remains elusive. Several host factors that are involved in this complex process were previously identified. Micro RNAs (miRNAs) are endogenous ∼22 ...nt RNAs that play important regulatory roles in a wide range of biological processes. Several studies demonstrated the clinical usefulness of miRNAs as diagnostic or prognostic biomarkers in various malignancies and in a few nonmalignant diseases. To study the role of miRNAs in the transition from latent to active TB and to discover candidate biomarkers of this transition, we used human miRNA microarrays to probe the transcriptome of peripheral blood mononuclear cells (PBMCs) in patients with active TB, latent TB infection (LTBI), and healthy controls. Using the software package BRB Array Tools for data analyses, 17 miRNAs were differentially expressed between the three groups (P<0.01). Hierarchical clustering of the 17 miRNAs expression profiles showed that individuals with active TB clustered independently of individuals with LTBI or from healthy controls. Using the predicted target genes and previously published genome-wide transcriptional profiles, we constructed the regulatory networks of miRNAs that were differentially expressed between active TB and LTBI. The regulatory network revealed that several miRNAs, with previously established functions in hematopoietic cell differentiation and their target genes may be involved in the transition from latent to active TB. These results increase the understanding of the molecular basis of LTBI and confirm that some miRNAs may control gene expression of pathways that are important for the pathogenesis of this infectious disease.
Abstract
The human pathogen
Mycobacterium tuberculosis
requires a P
1B
-ATPase metal exporter, CtpC (Rv3270), for resistance to zinc poisoning. Here, we show that zinc resistance also depends on a ...chaperone-like protein, PacL1 (Rv3269). PacL1 contains a transmembrane domain, a cytoplasmic region with glutamine/alanine repeats and a C-terminal metal-binding motif (MBM). PacL1 binds Zn
2+
, but the MBM is required only at high zinc concentrations. PacL1 co-localizes with CtpC in dynamic foci in the mycobacterial plasma membrane, and the two proteins form high molecular weight complexes. Foci formation does not require flotillin nor the PacL1 MBM. However, deletion of the PacL1 Glu/Ala repeats leads to loss of CtpC and sensitivity to zinc. Genes
pacL1
and
ctpC
appear to be in the same operon, and homologous gene pairs are found in the genomes of other bacteria. Furthermore, PacL1 colocalizes and functions redundantly with other PacL orthologs in
M. tuberculosis
. Overall, our results indicate that PacL proteins may act as scaffolds that assemble P-ATPase-containing metal efflux platforms mediating bacterial resistance to metal poisoning.
Iron, zinc and copper, among others, are transition metals with multiple biological roles that make them essential elements for life. Beyond the strict requirement of transition metals by the ...vertebrate immune system for its proper functioning, novel mechanisms involving direct metal intoxication of microorganisms are starting to be unveiled as important components of the immune system, in particular against Mycobacterium tuberculosis . In parallel, metal detoxification systems in bacteria have been recently characterized as crucial microbial virulence determinants. Here, we will focus on these exciting advancements implicating copper- and zinc-mediated microbial poisoning as a novel innate immune mechanism against microbial pathogens, shedding light on an emerging field in the metallobiology of host–pathogen interactions.
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