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.