If you have noted from my posts, I have been often talking about a TB especially in the last few posts. Recently as a part of my work, I have been talking to a person working on TB. One of his comment was that there is a lot of literature available on Tuberculosis. But a lot less is understood. Other than HIV and Influenza, TB would be yet another candidate that will keep the scientists the busy for years to come. Previously, I have noted that improvements have been made in form of new class of drugs (Link), search for vaccines etc (Link). However, the understanding of the infection process is still a big halo.
|Fig 1: PknG blocks phagosome-lysosome fusion.|
It has been very much clear from experiments and anecdotal findings that this isn't part of the full story. How does the bacteria coordinate this whole survival strategy. Notice from my above paragraph, the bacteria by itself doesn't invade the pulmonary tissue. It is the ability to survive inside the macrophages that carries them into deeper tissue, by a Piggy-back mechanism (You get my point).
First question that is asked would be, is Piggy-backing the tubercle bacilli just a matter of cell carrying it anywhere the cell wants to, or somehow directed by the bacilli itself. The latest study shows that perhaps it is pathogen directed. The study established that the pathogenic TB can recruit permissive macrophages to the site using a chemokine receptor 2 (CCR2)-mediated pathway. Furthermore it evades immunity with the help of a cell-surface-associated PDIM (Phthiocerol Dimycoceroserate) lipid which shields the underlying PAMPs. The paper challenged the common idea that alveolar surfaces of the distal lung offer a more favorable environment for mycobacterial proliferation. Instead what the study shows is that other members of normal flora can get the TLR signalling right which leads to clearing of organism. In contrast, alveolar micro-environment is sterile and thus gets the bacteria ample chance to multiply.
That leads me to think a couple of thoughts. Is there a similar comparable mechanism in Salmonella causing enteric fever, cause they too take a ride by resisting intracellular killing. 2nd question, If i could unmask the PDIM coat by perhaps inhibiting its synthesis, would that be the wonder drug for TB? Perhaps more research can tell
Das B, Kashino SS, Pulu I, Kalita D, Swami V, Yeger H, Felsher DW, & Campos-Neto A (2013). CD271(+) bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis. Science translational medicine, 5 (170) PMID: 23363977
Warner DF, & Mizrahi V (2007). The survival kit of Mycobacterium tuberculosis. Nature medicine, 13 (3), 282-4 PMID: 17342138
Wong D, Bach H, Sun J, Hmama Z, & Av-Gay Y (2011). Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. PNAS, 108 (48), 19371-6 PMID: 22087003
Cambier CJ, Takaki KK, Larson RP, Hernandez RE, Tobin DM, Urdahl KB, Cosma CL, & Ramakrishnan L (2014). Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature, 505 (7482), 218-22 PMID: 24336213
Kugelberg E (2013). Immune evasion: Mycobacteria hide from TLRs. Nature reviews. Immunology. doi:10.1038/nri3604