“I really don’t know how to approach this piece anymore!” I sighed to Anna, The Schuh Store’s (as I affectionately know my lab!) summer research intern. “The best I came up with, for a title, was Caged Heat, like the Jon Demme prison movie, given how granulomas are sort-of-prisons with that level of theatrical intrigue, but prison porn is hard to sell on a microbiology blog!”
“Yeah, don’t do that,” Anna said with the pragmatic laconicism that I have come to adore.
“I was also thinking of using a Death Star analogy, but that is so untenably geeky!” I reasoned.
“You are wearing a Star Wars shirt,” Anna pointed out.
“Oh, fine!” I ejaculated. “But, seriously, the first draft was pretentious and very “I-talk-to-friends-about-science-over-Martinis” which may lead people to believe that I haven’t really traversed past the imaginary friend phase…”
“Ah, but have you?” She asked. “Um, why don’t you just talk about them? The granulomas? If you find them fascinating, just talk about them! You don’t need a gimmick!”
“Maybe the lack of a gimmick is, in itself a gimmick?” I wondered out aloud. “Maybe I’ll use this conversation…”
Trust me, constant readers, as much as I recognize that granulomas are too fantastic to be confined by ersatz analogies, this writer has to start somewhere!
Now, immunology changes, and so reveals that things never are as they once appeared. It’s a scary thought, in a way, wherein the cells that comprise you guard their own secrets so jealously…but, I digress! As far as granulomas are concerned, I belong to the school of thought that understood a granuloma to be a compact collective of hyper-activated macrophages that stood in a phalanx-formation of sorts, effectively confining tuberculosis-causing mycobacteria within, and curtailing further infection. This ebullient bro-down of macrophages is surrounded by a gallery of genteel lymphocytes that await antigen presentation so as to mobilize/amplify an adaptive response. It’s all so beautiful, systematic…and thusly, A Very Good Thing. Right? Well, as it turns out, the granuloma is the apotheosis of the expression: No good deed goes unpunished.
In an elegant experiment on zebrafish embryos, J.M. Davis and his team showed, in 2002, that granuloma formation did not require help from the adaptive immune system at all, for the zebrafish embryos infected by Mycobacterium marinum lacked lymphocytes altogether. It was later shown that the Mycobacterium gene locus, RD-1, which, when deleted, leads to a bacterium enervated enough to be used as a live vaccine, was the arbiter of the intrigue that leads one to question the role of the granuloma in tuberculosis. The RD-1 gene locus is a beautiful/diabolical (however you choose to see it!) example of how the effective “arms race” between host and pathogen escalates and keeps things interesting. This gene locus encodes a Type VII secretion system called ESX-1 which, as secretion systems do, secretes the imaginatively named Early Secreted Antigen 6 (ESAT6). ESAT6 finds a place in a lot of mycobacterial subterfuges such as inducing apoptosis, pore formation, the evasion of phagosomes and the recruitment of macrophages.
It is the last item on that list that is of interest to us in the context of granulomas. ESAT6 is, essentially, a signalling molecule, which signals the induction of apoptosis in an infected macrophage, and is thus released such that it can interact with surrounding epithelial cells. Here, it signals the epithelial cells to upregulate the production of Matrix Metalloproteinase 9 (Mmp9). Note that this is the host’s Mmp9, and it serves to recruit more uninfected macrophages to the granuloma, and thus the granuloma grows…
Mycobacteria use both apoptosis and necrosis to their advantage so as to further their pathogenic agenda. Caseating necrosis (wherein the granuloma appears to be congealing like cheese, and hence the ‘caseous’ appearance) is a definitive feature of an active tuberculosis infection, and the bacteria found in the cheesy necrotic exudate are, for one, a very large population, and secondly, capable of mass infecting an equally large number of cells. Apoptosis, on the other hand, is used much more systematically, wherein infected debris from apoptotic macrophages is taken up by the naïve macrophages (those that showed up there thanks to Mmp9), and the bacteria spread through the granuloma.
Remember the perimeter of lymphocytes that surrounds the granuloma? Well, infected macrophages are rendered unable to respond to T-cell help and/or just incapable of presenting antigen to T-cells in good time. This delay makes all the difference between an infection that persists and one that can be cleared away quickly before lasting damage is done.
Mycobacteria, thus, turn a host defense strategy into a Trojan Horse of sorts, and hoodwink the most vigilant of the immune system’s sentinels. Who wins this internal Iliad-inspired conflict depends entirely on how immunocompetent the individual is.
It is my belief that these investigations are vital since Tuberculosis is poised to make a comeback, and we have exhausted our armoury as far as current drugs go. Understanding the ploys and wiles employed by both host and pathogen will serve to develop more effective means, be it via immune-therapy or new therapeutic targets, against yet another TB epidemic.
My main reference was a wide-ranging review by Dr. Lalita Ramakrishnan in May 2012’s Nature Reviews: Immunology. It talks in explicit detail about a lot of the items touched upon here, and some that have not, but are just as cool!
The zebrafish experiment, by J.M. Davis et al, can be found in Immunity 17, 2002. pp 693-702.
The role of the RD-1 gene locus is eloquently explicated by H.E. Volkman et al in PLoS Biol 2, 2004. pp 92-95.