Are mycobacteria calling the shots in human infections?

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Are mycobacteria calling the shots in human infections?

M tuberculosis phagocytosis by a macrophage (source)

M tuberculosis phagocytosis by a macrophage (source)

Our eye has recently been drawn to 2 papers from Lalita Ramakrishnan's laboratory, both using the zebrafish larvae in vivo model to focus on the role of mycobacterial phenolic glycolipids (PGLs) in orchestrating the host immune response following infection with Mycobacterium marinum or Mycobacterium leprae.

The first paper was presented by Carolin Turner in our group's journal club last week, and demonstrated that PGLs expressed on M marinum directs infected resident macrophages to secrete CCL2, recruiting CCR2-expressing monocytes to the site of infection. Amazingly, these same cells that are recruited are more permissive to bacterial replication, thus seemingly favouring bacterial survival in the host.

Concurrently, the same group published a paper in Cell demonstrating that PGL expression by M leprae was responsible for macrophage activation, reactive nitrogen species generation and consequent nerve damage, a feature characteristic of most clinical presentations of leprosy.

As ever, even elegant studies such as these, when performed in animal models raise questions about how the findings translate to a natural infection in humans. It is notable that the clarity (literally) offered by transparent zebrafish larvae is offset by the lack of any adaptive immune response at the time the experiments were performed. Thus, we do not know how a T cell response, ubiquitous in mycobacterial infections, would tip the balance in the host-pathogen interactions described.

Nevertheless, it is striking how mycobacterial surface glycoproteins can apparently drive the pathogenesis of infection with seeming impunity. SImilar to immune evasive actions of PGLs described here, another virulence factor expressed by M tuberculosis, ESAT-6, can provide the bacteria a mechanism to escape the hostile phagolysosome. Overall, these findings would suggest that studying the biology of different clinical strains of pathogenic mycobacteria may yield significant information on the determinants of disease in humans, and thus complement well the work of those of us focusing predominantly on the host's attempt to contain the infection. In some instances, it may be that from the moment the bacteria arrive, the host's fate is already out of their control.

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Meeting report: 10th International Conference on the Pathogenesis of Mycobacterial Infections

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Between 23rd and 25th August 2017, we attended the 10th International Conference on the Pathogenesis of Mycobacterial Infections meeting in Stockholm. It was a small gathering (100 or so attendants) but over 2 days a large number of topics were covered. Below are a few of our (probably biased!) highlights:

Day 1 kicked off with a keynote address from Joel Ernst, who underlined the importance of focusing on diversity in host response to Mycobacterium tuberculosis (Mtb) infection (clinical & immunological in order to determine the critical determinants of clinical outcome in tuberculosis infection. Gunilla Kallenius followed this up with a diagnostic orientated keynote address, readdressing diagnostic urinary lipoarabinomanna (LAM) detection in TB disease. She described how microbead concentration of LAM in urine may significantly increase the sensitivity of a diagnostic test who's use to date has been limited to confirmation of TB in patients coinfected with advanced HIV disease.

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The morning session on day 2 focused on mycobacterial biology, with our highlight being Roland Brosch who proposed a mechanism of action for a putative novel TB vaccine. He demonstrated that by lacking ESX-1 secretion system, BCG is unable to escape the phagolysosome and access the cytosol, in contrast to the ESX-1 expressing Mtb. Whilst this approach allows the bacteria to escape the phagolysosome environment, it results in triggering of cGAS and an ensuing type I IFN and inflammasome driven response. He demonstrated that transfecting the Mycobacterium marinum ESX-1 machinery into BCG generated a bacterial species of low virulence (like BCG) but with the ability to access the macrophage cytosol and trigger inflammation. Consequently he demonstrated that such a recombinant BCG was superior in protecting mice in a Mtb challenge model. We felt this was an innovative and exciting combination of bacterial biology and host response to guide both understanding of the host-pathogen interaction and also provide direct insight into putative new vaccine development.

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Another highlight of day 2 was Simone Joosten who described the phenotype of HLA-E restricted T cells present in active TB diseae, which carry an unusual phenotype in that they have cytolytic ability but secrete Th2 cytokines. This perked our interest as Th2 responses in the context of Tb are rare. However, in our own work looking at inflammation at the site of TST challenge, we were also surprised to observe enrichment of Th2 responses in the context of unmasking TB-IRIS. In this setting, we surmised that these responses may be responsible for driving the IRIS pathology, and it would be of interest to see if this was coupled by the presence of the same HLA-E restricted T cells described by Simone. 

Obviously our day 3 highlight was our own Gabriele Pollara presenting work on IL-17-driven pathogenic immune responses in TB disease (manuscript on its way, we promise!), but in fact the morning session was filled with other interesting talks. Adrian Martineau provided a highly humorous and informative run through his extensive and thorough efforts to explore a role for Vitamin D in tuberculosis infection. He reminded us that Vitamin D attenuates inflammatory responses to TB in vitro, but also that this has yet to translate to clinical benefit in active TB or prevention of disease in those with latentinfection.

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Finally Deepak Kashaul showed some new and exciting data that blockade of the hose IDO enzyme in the macaque model of TB infection could remove an immunosuppressive block on granuloma T cells to access the bacteria-rich core of the granuloma. He acknowledged limitations that this was a low dose challenge experiment (i.e. not full blown active disease) and that this may have prevented significant levels of immunopathology using this approach. Nevertheless, this was an elegant demonstration of the power of performing host-directed intervention studies in the context of challenge experiments in an animal model most aligned to immunopathology in humans. In turn, the findings from this study may directly inform clinical therapeutic options in man more readily.

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