The impact of mucosal infections on acquiition and progress of tuberculosis

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The impact of mucosal infections on acquisition and progression of tuberculosis
S Perry1, R Hussain2 and J Parsonnet1
More than one-third of the world’s population, or over 2 billion people, are infected with Mycobacterium tuberculosis, the causativepathogen of tuberculosis in humans. Why only 10% of those infected develop active disease while the remainder harbor latent infection remains one of the greatest scientific and public health mysteries. Bacterial persistence is characterized by a dynamic state of immunological tolerance between pathogen and host. The critical role of CD4 + T cells in defense against intracellular pathogens becameevident during epidemiological studies of HIV-1 infection, which showed a clear inverse relationship between CD4 + T-cell count in peripheral blood and increased risk of infection with M. tuberculosis, pneumocystis and Toxoplasma gondii. There is also growing evidence of a common mucosal immune system, whereby immune cells activated at one mucosal site may disseminate to remote effector sites. Inthis commentary, we review emerging evidence from human studies that the outcome of M. tuberculosis infection is influenced by concurrent mucosal infections, using Helicobacter pylori and geohelminths as examples. Understanding how the complexity of microbial exposures influences host immunity may have important implications for vaccine development and therapeutic interventions.

INTRODUCTIONThe mucosa of the gastrointestinal and respiratory tracts comprise the largest surfaces in contact with the external milieu. This system is designed to provide a physico-chemical barrier against

dissemination of pathogenic mircroorganisms while sampling a vast array of foreign antigens, presenting them to the immune system, and adapting them to the presence of foreign microbial communities.1 Inaddition to pattern recognition

and secretory antibody defenses, mucosalassociated lymphoid tissue (MALT)— populated by distinct dendritic, T, B, and accessory cell populations—acts as an inductive tissue for priming of antigen-presenting cells at remote effector sites via the “common mucosal immune system”.2,3 Gut-associated lymyphoid tissue—the subset of MALT that exists in thegastrointestinal tract—is a major site for induction of T regulatory cells necessary for microbial tolerance.4 With recognition of the common mucosal immune system and its unique properties, the development of mucosal vaccines and therapies has become an area of intense research interest.2,5,6 In this commentary, we briefly review epidemiological evidence that the clinical outcome of the respiratory infectioncaused by Mycobacterium tuberculosis may be modulated by mucosal infections that are endemic in the same populations. As examples, we focus on Helicobacter pylori and gastro-intestinal helminthiasis, two major gut-associated “pathobiontic” infections that frequently co-exist in TBinfected hosts (Figure 1). We propose that colonization with these pathogens exerts competitive effects on regulationof the immune response to M. tuberculosis: H. pylori promoting a Th1-type response consistent with control of TB, and helminthiasis promoting a Th2-type response that may disregulate responses to tuberculosis (TB). In each case, the newly recognized Th17 lineage7–10 may also have a role. These lines of investigation are just beginning, and further mechanistic as well as immuno-epidemiologicalresearch is needed. Understanding how common, naturally occurring mucosal infections influence immunity to TB may lead to further insights into the therapeutic properties of the common mucosal immune system.

1Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA. 2Department of Molecular Biology, Aga Khan University, Karachi, Pakistan. Correspondence: S...
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