Interaction of pathogenic mycobacteria with the host immune system

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Pathogenic mycobacteria, in particular Mycobacterium tuberculosis, the causative agent of tuberculosis, have the remarkable capacity to circumvent destruction within one of the most hostile cell types of a vertebrate host: the macrophage. The ability of pathogenic mycobacteria to survive inside macrophages has been known for more than 30 years; yet, only recently have advances in molecular genetics, biochemistry, immunology, as well as global analysis of gene expression, started to unravel the strategies utilized by these pathogens for intracellular persistence. In addition, the definition of key molecules that are important for intracellular survival opens the possibility to develop new drugs to combat mycobacterial diseases.

Introduction

We are exposed to a plethora of microbes that continuously invade our organs, both for our benefit, as in the case of commensals, and to our potential detriment, as in the case of pathogens. Selective pressure has ensured the development of a well-functioning immune system that is able to eradicate almost all incoming bacteria, parasites and viruses. However, there are a few species that have acquired the ability to evade the immune system and are of major concern because these are pathogens that can cause disease and death. Of these, pathogenic mycobacteria such as Mycobacterium tuberculosis have been among the most successful ones, with an annual burden of 8 million cases of disease, resulting in 2 million deaths (http://www.who.int/tb/en/).

The success of pathogenic mycobacteria is largely attributed to their capacity to avoid destruction within host immune cells, in particular macrophages. Mycobacteria are efficiently internalized into macrophage phagosomes by many different receptors. However, in contrast to the normal course of events during which the phagocytosed cargo is shuttled to lysosomes where it is efficiently destroyed, following uptake, mycobacteria are able to block their delivery to lysosomes. In so doing, these pathogens manage to circumvent immediate destruction, enabling them to establish a niche inside the macrophage, where they can survive and even replicate. In addition, it is becoming clear that in order to persist within this host cell, pathogenic mycobacteria must be able to prevent the activation of macrophages.

This review summarizes recent developments contributing to our understanding of how pathogenic mycobacteria manipulate the host to establish an infection.

Section snippets

Host factors modulating mycobacterial trafficking

Entry of mycobacteria into phagocytic cells can occur through binding to multiple receptors, all leading to the delivery of the bacilli into macrophage phagosomes. Although the precise receptor that mediates mycobacterial uptake in vivo is yet to be established, multiple molecules have been shown to trigger phagocytosis in vitro. A Drosophila RNA-interference screen has now added a member of the CD36 family of scavenger receptors to the list of receptors identified as being important for

Proteins

Which mycobacterial proteins have thus far been implicated in blocking the transfer of mycobacteria from phagosomes to lysosomes? Firstly, M. tuberculosis secretes an acid phosphatase (SapM), which is similar to eukaryotic acid phosphatases and might be responsible for the above-mentioned PtdIns-3P depletion at the mycobacterial phagosome [10•, 13], thus blocking the association of FYVE proteins with phagosomes.

Secondly, a eukaryotic-like serine/threonine kinase, protein kinase G (PknG),

Cross-talk with host immunity

Infection with mycobacteria, as is the case for infection with many other microbes, is accompanied by activation of the immune system through different signaling cascades. It turns out that pathogenic mycobacteria can influence the outcome of such immune cell activation at different levels. Here, we focus on recent developments in understanding of how mycobacteria alter their intracellular fate by modulating immune responses.

Toll-like receptor signaling

Toll-like receptors (TLRs) mediate the activation of cells of the innate immune system, resulting in destruction of the invading microbes through the activation of several signaling cascades. TLRs signal either in a MyD88-dependent or MyD88-independent manner, leading to the nuclear translocation of nuclear factor-κB. Nuclear factor-κB is a transcription factor involved in the expression of many immune response genes, such as those encoding the cytokines tumor necrosis factor-α and

Host regulators of innate immune responses

An important macrophage-activating molecule involved in the immune defense against pathogenic mycobacteria is interferon-γ (IFN-γ). Both mice and humans with genetic defects in IFN-γ signaling are highly susceptible to mycobacterial diseases. Several immune mechanisms, such as antigen presentation, leukocyte–endothelium cell interactions, cell growth and apoptosis, reactive nitrogen and oxygen intermediates as well as phagosome–lysosome fusion can be modulated through the activity of IFN-γ.

Events in the granuloma

Following phagocytosis and replication of pathogenic mycobacteria within macrophages, the infected cells migrate into tissues where additional immune cells are recruited to form a granuloma; this consists predominantly of T cells and M. tuberculosis-infected macrophages. The granuloma subsequently develops central areas of necrosis (called caseum, from the word ‘cheese’), resulting in the death of the majority of the bacteria and destruction of the surrounding host tissue. The surviving bacilli

Conclusions and perspectives

Pathogenic mycobacteria continue to elude us at several levels. These microbes appear to harbor specialized secretion machineries not previously seen in any other microbe, to mimic eukaryotic signal transduction cascades and to have an almost endless number of strategies for tricking the host's immune system. Nevertheless, concerted efforts over the past few years have started to lead to a better insight into some of the mycobacterial strategies. Importantly, there seems to be a spin-off in

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Christoph Dehio and members of the Pieters’ laboratory for critical reading of this manuscript. Work in the laboratory of JP is supported by the Swiss National Science Foundation, The World Health Organization and the Swiss Life Jubileum fund. ENGH is a recipient of a FEBS Fellowship.

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