Trends in Microbiology
What's good for the host is good for the bug
Introduction
Mycobacterium tuberculosis is a well-adapted and very successful human pathogen. This organism is believed to have infected at least one-third of the current world's population. A subset of those people infected progress to primary tuberculosis, and approximately two million people per year die of this disease. However, most infections are controlled by the immune response and are asymptomatic; nonetheless, the bacilli persist in the host and this is termed latent tuberculosis. It is estimated that a latently infected person has a 10% lifetime chance of reactivating the latent M. tuberculosis infection and progressing to active tuberculosis. Only individuals with active tuberculosis are contagious and capable of infecting others. We believe that M. tuberculosis is dependent on inducing an immune response and subsequent immunopathology to provide a niche for survival and also to facilitate transmission to naïve hosts. Recent data strongly support a role for mycobacterial products in the regulation of the immune response, suggesting that induction of the immune response could be beneficial to the pathogen, as well as to the host.
Section snippets
Induction of the immune response to M. tuberculosis
The immune response to infection with M. tuberculosis involves a strong T-cell response, consisting of CD4 and CD8 T cells that can secrete interferon (IFN)-γ to activate macrophages, in conjunction with another signal, such as tumor necrosis factor (TNF; reviewed in Ref. [1]). The bacterium survives and grows within non-activated macrophages, but activated macrophages have various anti-mycobacterial mechanisms. CD8 T cells can kill infected macrophages and the bacteria within them using
Mycobacterial products influence induction of immune responses
M. tuberculosis interacts initially with alveolar macrophages and dendritic cells in the airways, and then with tissue and monocyte-derived macrophages as well as dendritic cells in the lungs. The interaction with these antigen-presenting cells (APCs) results in the production of inflammatory cytokines, including TNF and interleukin (IL)-12, as well as a variety of chemokines 4, 5. However, each of these cell types are likely to be distinct in their interaction with the bacillus, based on
Regulation of granuloma formation
TNF is a key cytokine for granuloma formation, and in mice that lack TNF or the TNF receptor, granuloma formation is aberrant or delayed, and M. tuberculosis infection is rapidly fatal 17, 18. In mice with chronic infection, neutralization of TNF results in loss of granuloma organization, aberrant pathology and subsequent death [19]. The significance of this cytokine in humans has only been revealed recently. It has been reported that treatment with TNF blockade using neutralizing antibodies in
Pathology and transmission: the key to successful pathogenesis
Pathology induced by a microbe is often associated with transmission to a new host. In the case of tuberculosis, transmission depends on adequate numbers of bacteria in the airways aerosolized by the cough or breathing of a person with active tuberculosis, and it stands to reason that those that cough out larger numbers of bacteria will be more contagious. In fact, numerous epidemiological and clinical data support a strong association between smear-positive tuberculosis patients (those with
Acknowledgements
We are indebted to Peter Small and Kathy DeRiemer for helpful discussion. We are grateful to David Russell, Elizabeth Rhoades, Michael Glickman, Steven Porcelli and Clifton Barry for providing data and information before publication. JoAnne L. Flynn is supported by the NIH (AI37859, AI47485, AI50732, HL71241, HL68526 and HL75845) and the American Lung Association (CI-016). John Chan is supported by the NIH (AI50732, HL71241 and HL68526).
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