Mycobacterium tuberculosis where is it found

They showed that deletion of hbhA from either M. Moreover, they showed that hbhA mutants had no phenotype whatsoever in J macrophage cells, but were impaired in their ability to infect A human lung epithelial cells, consistent with the role of this gene in cell adhesion.

Overall, these studies provide evidence for a direct role for epithelial cells in dissemination. The role of hbhA in dissemination across epithelial cells has since been confirmed in vitro using the polarized bilayer models described above Ryndak et al.

However, these experiments do not address whether dissemination is due to translocation across epithelial cells, or cell death. Purified recombinant HbhA binds to the surface of polarized epithelial cells, induces actin reorganization, and can be internalized into cytoplasmic vacuoles via endocytosis. However, HbhA does not disrupt the integrity of cellular tight junctions or affect the permeability of epithelial cell monolayers Menozzi et al.

Another possible route of passage across epithelial cells could be through specialized epithelial cells known as microfold cells, or M cells. M cells are part of the epithelial barrier in mucosa-associated lymphoid tissues MALT including the gut and some parts of the respiratory system. Although M cells form tight junctions with other epithelial cells and are part of the epithelial barrier, they play an active role in taking up antigens and delivering them across the epithelia to antigen-presenting cells Neutra et al.

Due to this unique ability, M cells have been shown to be exploited by a large number of bacterial intestinal pathogens to invade deeper tissues Owen et al. The first suggestion that mycobacteria could also be using M cells as a route across the epithelia came in , via demonstration of uptake of the M.

A similar role for pulmonary M cells was later demonstrated in the guinea pig model using virulent M. Additional evidence for the role of M cells in mycobacterial dissemination was provided more recently using the mouse model to demonstrate that depletion of M cells decreases dissemination to the cervical lymph nodes, and an in vitro model using Caco-2 epithelial cells to show increased translocation when M cells are co-cultured in the monolayers Nair et al.

Taken together, these studies suggest that M cells are capable of translocating M. The only downside to this model of dissemination is that the prevalence of M cells in the human lung epithelium is unclear. Both nasal-associated lymphoid tissues NALT and bronchus-associated lymphoid tissues BALT are present in rodent models, but very little is known about these tissues in healthy human adults. They have been described as being primarily present in childhood and subsequently receding, perhaps inducible in response to infection or inflammation or only sparsely present Bienenstock and McDermott, Therefore, it remains somewhat unclear what role M cells play in M.

Another candidate cell population suggested to play a role in M. These cells are particularly attractive candidates due to the established role of dendritic cells in active transport of antigens to the lymph nodes.

Therefore, dendritic cells could provide a potential route of dissemination out of the primary site of infection for M. Importantly, iDCs in dendritic cell reporter mice infected with BCG also migrate to peripheral sites at a much higher rate than in uninfected mice Schreiber et al.

Harding et al. Although these experiments establish a link between dendritic cells and dissemination, they have all been performed in mouse models that do not form structurally similar primary and secondary granulomas to those observed in humans. Many of these experiments also used the model organism M. Interestingly, both human and mouse dendritic cell migration decreases across an epithelial barrier toward lymphatic chemokines following infection with the attenuated M. However, a computational model extrapolated from a data set consisting of blood and lung samples of non-human primates infected with the Erdman strain of M.

Cleret et al. Subsequent studies suggest similar roles for DCs in trafficking Streptococcus pneumoniae and Francisella tularensis from initial infection sites in the lungs to the lymphatic system as well as roles for DCs in systemic dissemination of Burkholderia pseudomallei and Salmonella typhimurium Bar-Haim et al.

Taken together, these studies suggest that dendritic cells play a prominent role in bacterial dissemination and that this may be a conserved mechanism across bacterial species. Extrapulmonary tuberculosis accounts for a relatively small percentage of human tuberculosis cases in immunocompetent adults. However, the clinical impact of extrapulmonary tuberculosis is larger than this statistic may suggest as extrapulmonary infections are some of the most difficult to diagnose and treat.

The gold standard for diagnosis of tuberculosis in many countries with the highest tuberculosis burdens remains sputum smear microscopy, but patients with extrapulmonary infections do not necessarily have bacteria in their sputum. Other assays that can be used to test for exposure to mycobacterial antigens, such as the tuberculin skin test and the QuantiFERON blood test are limited due to cross-reactivity with the BCG vaccine or environmental mycobacteria, respectively, and thus cannot be used to diagnose clinical tuberculosis.

In , GeneXpert was introduced and recommended by the WHO for pulmonary infections, but although this has the potential to address diagnostic challenges the test requires sophisticated and expensive equipment that is not always available in the places it is most needed and remains a sputum-based test Walzl et al.

Overall, this means that diagnosis strategies are lacking for extrapulmonary infections. The wide range of sites and symptoms associated with extrapulmonary tuberculosis means that it can masquerade as a number of different diseases and syndromes, such that tuberculosis may not even be suspected and tested for, delaying the time before appropriate treatment can be provided.

Even when extrapulmonary tuberculosis is diagnosed in a timely manner, the recommended treatment regimen are primarily designed against pulmonary tuberculosis, and may or may not be effective depending on the presentation of extrapulmonary disease.

Extrapulmonary tuberculosis is associated with particularly high morbidity and mortality. This may be due to the fact that extrapulmonary forms of the disease often occur in some of the most vulnerable patients including young children and immunocompromised individuals. However, while they are no longer the death sentence that they once were, certain forms of extrapulmonary tuberculosis, particularly infection of the central nervous system such as meningitis and miliary tuberculosis, have very poor clinical outcomes.

As most tuberculosis infections are contracted through the inhalation of aerosols containing M. Secondary pulmonary granulomas are formed through reseeding of the lungs through the bloodstream.

Therefore, understanding dissemination has broad implications for tuberculosis treatment and prevention. If these early steps can be blocked through vaccination or early intervention, it is conceivable that not only could extrapulmonary infections be prevented, but that reseeding the lungs could be blocked.

This hypothesis is supported by the success of therapeutics designed to target the first known M. Immunization with purified recombinant HbhA protects mice from infection with M. Boosting with this antigen also improves the efficacy of the BCG vaccine, suggesting a combined regimen has the potential to protect against dissemination Guerrero et al.

HbhA has also been investigated as a potential diagnostic antigen and biomarker De Maio et al. It is not unreasonable to think that identification and characterization of additional dissemination factors could lead to the development of equally successful vaccines and therapeutics. However, since the identification of HbhA, research in this area has resulted in only a few new candidates being identified.

Further investigation into identifying mycobacterial dissemination factors is needed. Identification of a comprehensive set of M. More sophisticated tracking of dissemination in vivo using modern imaging techniques could allow analysis of the longstanding belief that dissemination occurs via the lymphatic and circulatory systems.

Moreover, further investigations into the interactions of M. Guidance on the future of M. The route through which enteric pathogens such as Salmonella typhimurium disseminate across the intestinal endothelial barrier to infect other tissues was once a hotly debated topic in bacteriology.

Closely paralleling the current state of understanding of M. This debate was eventually addressed through experiments using bacterial genetics to address each hypothesis. First, S. A subsequent study showed that if all proposed epithelial cell adhesins were deleted from S. Moreover, if the triple mutant was used to infect CD18 KO mice that lack a surface antigen expressed by macrophages and dendritic cells that dissemination to the liver and spleen was greatly reduced compared to wild-type mice Garcia de Viedma et al.

From these combined studies, it can be concluded that neither of these proposed mechanisms are mutually exclusive, and that S. To bring a similar sense of conclusion to the M. Using the history of enteric pathogen dissemination as a lesson, it seems likely that none of the proposed theories are mutually exclusive and that future evidence may reveal that mycobacteria are capable of utilizing more than one strategy to disseminate and establish extrapulmonary infections. MM wrote the article and prepared the figures.

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