scholarly journals Understanding Metabolic Regulation Between Host and Pathogens: New Opportunities for the Development of Improved Therapeutic Strategies Against Mycobacterium tuberculosis Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Ji-Hae Park ◽  
Dahee Shim ◽  
Keu Eun San Kim ◽  
Wonsik Lee ◽  
Sung Jae Shin
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Cells ◽  
Protective Immunity ◽  
Metabolic Regulation ◽  
Therapeutic Strategies ◽  
Host Cells ◽  
Mycobacterium Tuberculosis Infection ◽  
Disease Outcomes ◽  
Granulomatous Lung Disease ◽  
Metabolic Conditions

Mycobacterium tuberculosis (Mtb) causes chronic granulomatous lung disease in humans. Recently, novel strategies such as host-directed therapeutics and adjunctive therapies that enhance the effect of existing antibiotics have emerged to better control Mtb infection. Recent advances in understanding the metabolic interplay between host immune cells and pathogens have provided new insights into how their interactions ultimately influence disease outcomes and antibiotic-treatment efficacy. In this review, we describe how metabolic cascades in immune environments and relevant metabolites produced from immune cells during Mtb infection play critical roles in the progression of diseases and induction of anti-Mtb protective immunity. In addition, we introduce how metabolic alterations in Mtb itself can lead to the development of persister cells that are resistant to host immunity and can eventually evade antibiotic attacks. Further understanding of the metabolic link between host cells and Mtb may contribute to not only the prevention of Mtb persister development but also the optimization of host anti-Mtb immunity together with enhanced efficacy of existing antibiotics. Overall, this review highlights novel approaches to improve and develop host-mediated therapeutic strategies against Mtb infection by restoring and switching pathogen-favoring metabolic conditions with host-favoring conditions.

scholarly journals Vaccine-Elicited 10-Kilodalton Culture Filtrate Protein-Specific CD8+ T Cells Are Sufficient To Mediate Protection against Mycobacterium tuberculosis Infection

2008 ◽  
Vol 76 (5) ◽  
pp. 2249-2255 ◽  
Author(s):  
Ying Wu ◽  
Joshua S. Woodworth ◽  
Daniel S. Shin ◽  
Sheldon Morris ◽  
Samuel M. Behar
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Culture Filtrate ◽  
Protective Immunity ◽  
Protective Antigen ◽  
T Cell Response ◽  
Rapid Expansion ◽  
Mycobacterium Tuberculosis Infection ◽  
Infected People ◽  
Culture Filtrate Protein

ABSTRACT The 10-kDa culture filtrate protein (CFP-10) and 6-kDa early secretory antigen of T cells (ESAT-6) are secreted in abundance by Mycobacterium tuberculosis and are frequently recognized by T cells from infected people. The genes encoding these proteins have been deleted from the genome of the vaccine strain Mycobacterium bovis bacillus Calmette-Guérin (BCG), and it is hypothesized that these proteins are important targets of protective immunity. Indeed, vaccination with ESAT-6 elicits protective CD4+ T cells in C57BL/6 mice. We have previously shown that M. tuberculosis infection of C3H mice elicits CFP-10-specific CD8+ and CD4+ T cells. Here we demonstrate that immunization with a CFP-10 DNA vaccine stimulates a specific T-cell response only to the H-2Kk-restricted epitope CFP-1032-39. These CFP-1032-39-specific CD8+ cells undergo a rapid expansion and accumulate in the lung following challenge of immunized mice with aerosolized M. tuberculosis. Protective immunity is induced by CFP-10 DNA vaccination as measured by a CFU reduction in the lung and spleen 4 and 8 weeks after challenge with M. tuberculosis. These data demonstrate that CFP-10 is a protective antigen and that CFP-1032-39-specific CD8+ T cells elicited by vaccination are sufficient to mediate protection against tuberculosis.

scholarly journals Mycobacterium tuberculosis infection of host cells in space and time

2019 ◽  
Vol 43 (4) ◽  
pp. 341-361 ◽  
Author(s):  
Claudio Bussi ◽  
Maximiliano G Gutierrez
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Cell Biology ◽  
Current Knowledge ◽  
Bacterial Pathogen ◽  
Infectious Agent ◽  
Host Cells ◽  
Cellular Mechanisms ◽  
Mycobacterium Tuberculosis Infection ◽  
Human Host

ABSTRACTTuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains one of the deadliest infectious diseases with over a billion deaths in the past 200 years (Paulson 2013). TB causes more deaths worldwide than any other single infectious agent, with 10.4 million new cases and close to 1.7 million deaths in 2017. The obstacles that make TB hard to treat and eradicate are intrinsically linked to the intracellular lifestyle of Mtb. Mtb needs to replicate within human cells to disseminate to other individuals and cause disease. However, we still do not completely understand how Mtb manages to survive within eukaryotic cells and why some cells are able to eradicate this lethal pathogen. Here, we summarise the current knowledge of the complex host cell-pathogen interactions in TB and review the cellular mechanisms operating at the interface between Mtb and the human host cell, highlighting the technical and methodological challenges to investigating the cell biology of human host cell-Mtb interactions.

scholarly journals CBA/J mice generate protective immunity to soluble Ag85 but fail to respond efficiently to Ag85 during natural Mycobacterium tuberculosis infection

2012 ◽  
Vol 42 (4) ◽  
pp. 870-879 ◽  
Author(s):  
Gillian L. Beamer ◽  
Joshua Cyktor ◽  
David K. Flaherty ◽  
Paul C. Stromberg ◽  
Bridget Carruthers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Protective Immunity ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Lanbo Shi ◽  
Qingkui Jiang ◽  
Yuri Bushkin ◽  
Selvakumar Subbian ◽  
Sanjay Tyagi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Cells ◽  
Aerobic Glycolysis ◽  
Defense Responses ◽  
Bioactive Lipids ◽  
Macrophage Infection ◽  
Mycobacterium Tuberculosis Infection ◽  
Metabolic Switch ◽  
Content Type ◽  
M1 Polarization

ABSTRACT Macrophages are the primary targets of Mycobacterium tuberculosis infection; the early events of macrophage interaction with M. tuberculosis define subsequent progression and outcome of infection. M. tuberculosis can alter the innate immunity of macrophages, resulting in suboptimal Th1 immunity, which contributes to the survival, persistence, and eventual dissemination of the pathogen. Recent advances in immunometabolism illuminate the intimate link between the metabolic states of immune cells and their specific functions. In this review, we describe the little-studied biphasic metabolic dynamics of the macrophage response during progression of infection by M. tuberculosis and discuss their relevance to macrophage immunity and M. tuberculosis pathogenicity. The early phase of macrophage infection, which is marked by M1 polarization, is accompanied by a metabolic switch from mitochondrial oxidative phosphorylation to hypoxia-inducible factor 1 alpha (HIF-1α)-mediated aerobic glycolysis (also known as the Warburg effect in cancer cells), as well as by an upregulation of pathways involving oxidative and antioxidative defense responses, arginine metabolism, and synthesis of bioactive lipids. These early metabolic changes are followed by a late adaptation/resolution phase in which macrophages transition from glycolysis to mitochondrial oxidative metabolism, with a consequent dampening of macrophage proinflammatory and antimicrobial responses. Importantly, the identification of upregulated metabolic pathways and/or metabolic regulatory mechanisms with immunomodulatory functions during M1 polarization has revealed novel mechanisms of M. tuberculosis pathogenicity. These advances can lead to the development of novel host-directed therapies to facilitate bacterial clearance in tuberculosis by targeting the metabolic state of immune cells.

scholarly journals Mycobacterium bovis BCG-Specific Th17 Cells Confer Partial Protection against Mycobacterium tuberculosis Infection in the Absence of Gamma Interferon

2010 ◽  
Vol 78 (10) ◽  
pp. 4187-4194 ◽  
Author(s):  
Teresa M. Wozniak ◽  
Bernadette M. Saunders ◽  
Anthony A. Ryan ◽  
Warwick J. Britton
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Th17 Cells ◽  
Protective Immunity ◽  
Bacterial Load ◽  
Gamma Interferon ◽  
Interleukin 17 ◽  
Mycobacterium Tuberculosis Infection ◽  
Significant Prolongation ◽  
Ifn Γ

ABSTRACT Protective immunity against tuberculosis (TB) requires the integrated response of a network of lymphocytes. Both gamma interferon (IFN-γ)- and interleukin 17 (IL-17)-secreting CD4+ T cells have been identified in subjects with latent TB infection and during experimental Mycobacterium tuberculosis infection, but the contribution of Th17 cells to protective immunity is unclear. To examine their protective effects in vivo, we transferred mycobacterium-specific IL-17- and IFN-γ-secreting CD4+ T cells isolated from M. tuberculosis BCG-immunized IL-12p40−/− and IFN-γ−/− or wild-type mice, respectively, into M. tuberculosis-infected IL-12p40−/− or RAG−/− mice. In the absence of IL-12 and IL-23, neither IL-17-secreting (Th17) nor IFN-γ-secreting (Th1) BCG-specific T cells expanded or provided protection against M. tuberculosis. In RAG−/− recipients with an intact IL-12/IL-23 axis, both Th17 and Th1 cells were activated and induced significant protection against M. tuberculosis. The reduction in the bacterial load following transfer of IFN-γ−/− Th17 cells was associated with significant prolongation of survival compared to recipients of naïve IFN-γ−/− T cells. This effect was at the cost of an increased inflammatory infiltrate characterized by an excess of neutrophils. Therefore, Th17 cells can provide IFN-γ-independent protection against M. tuberculosis, and this effect may contribute to the early control of M. tuberculosis infection.

scholarly journals Involvement of IL‐17A‐producing TCR γδ T cells in late protective immunity against pulmonary Mycobacterium tuberculosis infection

2016 ◽  
Vol 4 (4) ◽  
pp. 401-412 ◽  
Author(s):  
Masayuki Umemura ◽  
Yuko Okamoto‐Yoshida ◽  
Ayano Yahagi ◽  
Seigo Touyama ◽  
Susumu Nakae ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Protective Immunity ◽  
Γδ T Cells ◽  
Tuberculosis Infection ◽  
Mycobacterium Tuberculosis Infection

scholarly journals Mycobacterium tuberculosis Infection Drives Mitochondria-Biased Dysregulation of Host Transfer RNA–Derived Fragments

2020 ◽  
Author(s):  
Monika M Looney ◽  
Yin Lu ◽  
Petros C Karakousis ◽  
Marc K Halushka
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Messenger Rna ◽  
Noncoding Rna ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Transfer Rna ◽  
Host Cells ◽  
Analysis Tool ◽  
Mycobacterium Tuberculosis Infection ◽  
Micro Rnas

Abstract Background Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis, causes 10 million infections and 1.5 million deaths per year worldwide. The success of Mtb as a human pathogen is directly related to its ability to suppress host responses, which are critical for clearing intracellular pathogens. Emerging evidence suggests that key response pathways may be regulated by a novel class of small noncoding RNA, called transfer RNA (tRNA)–derived fragments (tRFs). tRFs can complex with Argonaute proteins to target and degrade messenger RNA targets, similarly to micro RNAs, but have thus far been overlooked in the context of bacterial infections. Methods We generated a novel miRge2.0-based tRF-analysis tool, tRFcluster, and used it to analyze independently generated and publicly available RNA-sequencing datasets to assess tRF dysregulation in host cells following infection with Mtb and other intracellular bacterial pathogens. Results We found that Mtb and Listeria monocytogenes drive dramatic tRF dysregulation, whereas other bacterial pathogens do not. Interestingly, Mtb infection uniquely increased the expression of mitochondria-derived tRFs rather than genomic-derived tRFs, suggesting an association with mitochondrial damage in Mtb infection. Conclusions tRFs are dysregulated in some, but not all, bacterial infections. Biased dysregulation of mitochondria-derived tRFs in Mtb infection suggests a link between mitochondrial distress and tRF production.

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