Mycobacterial Dormancy Systems and Host Responses in Tuberculosis.

Vidyullatha Peddireddy,Sankara Narayana Doddam,Niyaz Ahmed

doi:10.3389/fimmu.2017.00084

Abstract

Tuberculosis (TB) caused by the intracellular pathogen, Mycobacterium tuberculosis (Mtb), claims more than 1.5 million lives worldwide annually. Despite promulgation of multipronged strategies to prevent and control TB, there is no significant downfall occurring in the number of new cases, and adding to this is the relapse of the disease due to the emergence of antibiotic resistance and the ability of Mtb to remain dormant after primary infection. The pathology of Mtb is complex and largely attributed to immune-evading strategies that this pathogen adopts to establish primary infection, its persistence in the host, and reactivation of pathogenicity under favorable conditions. In this review, we present various biochemical, immunological, and genetic strategies unleashed by Mtb inside the host for its survival. The bacterium enables itself to establish a niche by evading immune recognition via resorting to masking, establishment of dormancy by manipulating immune receptor responses, altering innate immune cell fate, enhancing granuloma formation, and developing antibiotic tolerance. Besides these, the regulatory entities, such as DosR and its regulon, encompassing various putative effector proteins play a vital role in maintaining the dormant nature of this pathogen. Further, reactivation of Mtb allows relapse of the disease and is favored by the genes of the Rtf family and the conditions that suppress the immune system of the host. Identification of target genes and characterizing the function of their respective antigens involved in primary infection, dormancy, and reactivation would likely provide vital clues to design novel drugs and/or vaccines for the control of dormant TB.

Highlights

Tuberculosis (TB), a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb), is one of the major drivers of human mortality worldwide since many decades with an estimated global burden of 10.4 million new TB cases and 1.4 million TB deaths in the year 2015 [1]
Evidence for the ability of Mtb to inhibit apoptosis is indicated by (a) the promotion of development of CD8+ T cell responses by the Sec2A-deficient mutant strain of Mtb; (b) manipulation of eicosanoid metabolism of T cells [60]; (c) increased frequency of macrophage apoptosis, accelerated CD4+ and CD8+ T-cell responses, and enhanced control of bacterial burden in Alox5 (5-lipoxygenase, required for generation of LXA4) deficient mice infected with virulent Mtb [61]; and (d) enhanced susceptibility to Mtb infection due to polymorphisms in Alox5 and lta4h [62, 63]
Development of multidrug resistance by Mtb complicates the clinical interventions. Serious side effects such as nephrotoxicity, ototoxicity, and dysglycaemia due to the use of powerful anti-TB drugs such as aminoglycosides, ethionamide, and gatifloxacin are some of the indirect clinical implications caused by the ability of Mtb to acquire drug resistance [250]. Another clinical implication that is very serious is the re-emergence of TB when host immune responses fail in conditions such as HIV infection [237] and the increased risk of developing TB in patients treated with anti-tumor necrosis factor (TNF) [251]

Summary

INTRODUCTION

Tuberculosis (TB), a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb), is one of the major drivers of human mortality worldwide since many decades with an estimated global burden of 10.4 million new TB cases and 1.4 million TB deaths in the year 2015 [1]. Evidence for the ability of Mtb to inhibit apoptosis is indicated by (a) the promotion of development of CD8+ T cell responses by the Sec2A-deficient mutant strain of Mtb; (b) manipulation of eicosanoid metabolism of T cells [60]; (c) increased frequency of macrophage apoptosis, accelerated CD4+ and CD8+ T-cell responses, and enhanced control of bacterial burden in Alox (5-lipoxygenase, required for generation of LXA4) deficient mice infected with virulent Mtb [61]; and (d) enhanced susceptibility to Mtb infection due to polymorphisms in Alox and lta4h [62, 63] Another important mechanism by which Mtb enhances its survival in the host is to delay the expansion of Foxp3+ regulatory T (Treg) cells and thereby delay adaptive immunity [64].

A Perfect Storm?

Findings

CONCLUSION