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      Editorial: Causes for Increased Susceptibility to Mycobacterium tuberculosis – A Close View of the Immune System

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          Abstract

          Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world’s population is infected with Mycobacterium tuberculosis (M. tb), the etiological agent of TB. The World Health Organization estimates that about 8–10 million new TB cases occur annually worldwide, and the incidence of TB is currently increasing. In this context, TB is in the top three (with malaria and HIV), being the leading cause of death from a single-infectious agent, and approximately three million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening disease. A major underlying factor responsible for increased susceptibility to M. tb is co-infection with HIV and the subsequent acquired immune deficiency syndrome. As of 2010, an estimated 34 million people are living with HIV infection worldwide, with an additional 2.7 million people newly infected each year. Of those 34 million living with HIV, 22.9 million live in sub-Saharan Africa, a region where M. tb is endemic. One of the hallmarks of AIDS brought on by HIV infection is increased susceptibility to opportunistic infections, including M. tb. Individuals with type II diabetes and cigarette smokers are also increasingly susceptible to M. tb infection. Successful control of M. tb infection requires effective innate and adaptive immune responses inside the granuloma leading to either killing or inhibition in the growth of M. tb. This Research Topic is a compilation of original research findings and review articles that are mainly centered on the pathogenesis of TB and host immune responses against M. tb infection. The articles in this Research Topic include (a) Experimental findings describing how different subsets of primary human dendritic cells respond to M. tb infection (1). (b) A comprehensive review on the variety of mechanisms by which mycobacteria subverts the host immune responses and intracellular effector mechanisms, leading to successful survival of the pathogen (2). (c) Research article demonstrating that the mycobacterial gene, Rv1169c modifies the fatty acids in the cell wall of the pathogen, and induces necrosis in the host cells, thereby functioning as a virulence factor (3). (d) A hypothetical and theory-based article describing the particle size distribution of cough aerosols as an important predictor of primary upper airway disease and cervical lymphadenitis in exposed hosts. The authors of this study hypothesize that large droplet aerosols (>5 μm) containing M. tb will be deposited in the upper airway and this in turn can induce host immune responses without establishing infection (4). (e) Research findings that illustrate that IL-17 inhibits apoptosis of M. bovis BCG- or M. tb-infected macrophages thus hampering the ability of host cells to control bacterial growth (5). (f) Review article describing the direct and indirect mechanisms by which natural killer cells control M. tb infection, and the effects of glutathione in improving the functions of natural killer cells to control M. tb infection (6). Conflict of Interest Statement The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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          Mechanisms of Control of Mycobacterium tuberculosis by NK Cells: Role of Glutathione

          Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be one of the most prevalent infectious diseases in the world. There is an upward trend in occurrence due to emerging multidrug resistant strains and an increasingly larger proportion of immunocompromised patient populations as a result of the acquired immunodeficiency syndrome pandemic. The complex and often deadly combination of multidrug resistant M. tb (MDR-M. tb) along with human immunodeficiency virus (HIV) puts a significant number of people at high risk for pulmonary and extra-pulmonary TB without sufficient therapeutic options available. Natural killer (NK) cells and macrophages are major components of the body’s innate immune system, contributing significantly to the body’s ability to synergistically inhibit the growth of M. tb in immune compromised individuals lacking a sufficient T cell response. Direct mechanisms of control are largely through the secretory products perforin, granulysin, and granzymes, as well as multiple membrane-bound death receptors that facilitate target directed lysis. NK cells also have a role in indirectly stimulating an immune response through activation of macrophages and monocytes with multiple signaling pathways, including both reactive oxygen species and reactive nitrogen species. Glutathione (GSH) has been shown to play a part in inhibiting the growth of intracellular M. tb through bacteriostatic mechanisms. Enhancing cellular GSH through several cytokines and N-acetyl cysteine has been shown to increase these effects, at least in part, through their action on NK cells. Taken together, there is substantial evidence for a mechanistic correlation between NK cell activity and functionality in combating M. tb in HIV infection mediated through adequate GSH production and use.
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            Quantity and Quality of Inhaled Dose Predicts Immunopathology in Tuberculosis

            Experimental animal models of tuberculosis (TB) have convincingly demonstrated that inhaled dose predicts immunopathology and survival. In contrast, the importance of inhaled dose has generally not been appreciated in TB epidemiology, clinical science, or the practice of TB control. Infectiousness of TB patients has traditionally been assessed using microscopy for acid-fast bacilli in the sputum, which should be considered only a risk factor. We have recently demonstrated that cough aerosol cultures from index cases with pulmonary TB are the best predictors of new infection among household contacts. We suggest that cough aerosols of M. tuberculosis are the best surrogates of inhaled dose, and we hypothesize that the quantity of cough aerosols is associated with TB infection versus disease. Although several factors affect the quality of infectious aerosols, we propose that the particle size distribution of cough aerosols is an important predictor of primary upper airway disease and cervical lymphadenitis and of immune responses in exposed hosts. We hypothesize that large droplet aerosols (>5 μ) containing M. tuberculosis deposit in the upper airway and can induce immune responses without establishing infection. We suggest that this may partially explain the large proportion of humans who never develop TB disease in spite of having immunological evidence of M. tuberculosis infection (e.g., positive tuberculin skin test or interferon gamma release assay). If these hypotheses are proven true, they would alter the current paradigm of latent TB infection and reactivation, further demonstrating the need for better biomarkers or methods of assessing TB infection and the risk of developing disease.
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              PE11 (Rv1169c) selectively alters fatty acid components of Mycobacterium smegmatis and host cell interleukin-6 level accompanied with cell death

              PE/PPE family proteins, named after their conserved PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains of N-terminal, are most intriguing aspects of pathologic mycobacterial genome. The roles of most members of this family remain unknown, although selected genes of this family are related to the virulence of Mycobacterium tuberculosis. In order to decipher the role of Rv1169c, the Mycobacterium smegmatis strain heterologous expressed this ORF was constructed and identified that Rv1169c was a cell wall associated protein with a novel function in modifying the cell wall fatty acids. The growth of Rv1169c expressing strain was affected under surface stress, acidic condition and antibiotics treatment. M. smegmatis expressing Rv1169c induced necrotic cell death of macrophage after infection and significantly decreased interlukin-6 production compared to controls. In general, these results underscore a proposing role of Rv1169c in virulence of M. tuberculosis, as it's role in the susceptibility of anti-mycobacteria factors caused by modified cell wall fatty acid, and the induced necrotic cell death by Rv1169c is crucial for M. tuberculosis virulence during infection.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/120423
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                22 October 2015
                2015
                : 6
                : 545
                Affiliations
                [1] 1Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences , Pomona, CA, USA
                Author notes

                Edited and reviewed by: Heinrich Korner, Menzies Research Institute Tasmania, Australia

                *Correspondence: Vishwanath Venketaraman, vvenketaraman@ 123456westernu.edu

                Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2015.00545
                4617100
                f4d1cb48-835a-4b02-9463-52e58695145f
                Copyright © 2015 Venketaraman.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 September 2015
                : 09 October 2015
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 6, Pages: 2, Words: 854
                Categories
                Immunology
                Editorial

                Immunology
                tuberculosis,host–pathogen interactions,host immune responses,pathogenesis,adaptive immunity

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