A new unifying theory of the pathogenesis of tuberculosis

Abstract

It is set in stone that Mycobacterium tuberculosis is a facultative intracellular bacterial parasite. This axiom drives our knowledge of the host response, the way we design vaccines against the organism by generating protective T cells, and to a lesser extent, the way we try to target anti-microbial drugs. The purpose of this article is to commit total heresy. I believe that M. tuberculosis can equally well be regarded as an extracellular pathogen and may in fact spend a large percentage of its human lung "life-cycle" in this environment. It is of course intracellular as well, but this may well be little more than a brief interlude after infection of a new host during which the bacterium must replicate to increase its chances of transmission and physiologically adapt prior to moving back to an extracellular phase. As a result, by focusing almost completely on just the intracellular phase, we may be making serious strategic errors in the way we try to intervene in this pathogenic process. It is my opinion that when a TB bacillus enters the lungs and starts to reside inside an alveolar macrophage, its central driving force is to switch on a process leading to lung necrosis, since it is only by this process that the local lung tissue can be destroyed and the bacillus can be exhaled and transmitted. I present here a new model of the pathogenesis of the disease that attempts to unify the pathogenic process of infection, disease, persistence [rather than latency], and reactivation.

Keywords: Latency; Persistence; Reactivation; Tuberculosis.

Fig.1

[A] In the first stage of the infection process an alveolar macrophage engulfs a bacterium [“B”, or possibly a clump/cluster, see text]. The cell then extends its cytoplasm and spreads across the alveolar epithelial surface. Soon afterwards [perhaps involving the use of their ESX system peptides?] the bacilli somehow cross the basal membrane [panel B]. This creates local inflammation and swelling between the alveolar epithelium and the capillary endothelium allowing the influx of tissue fluid. This in turn allows the influx of macrophages and neutrophils from the blood, and dendritic cells from the lung parenchyma.

Fig.2

Initial infection now triggers a considerable influx of cells which creates an initial lesion or infectious focus. In most cases the incoming macrophages kill the bacteria but when this fails the bacteria multiply and these macrophages are themselves killed, releasing bacteria [arrow]. Released bacilli are probably at this stage phagocytosed by newly arriving cells, amplifying the process. At this point the influx is predominantly macrophages, with some neutrophils and a smaller number of lymphocytes. The neutrophils produce and secrete oxygen radicals and while this probably has little impact on the mycobacteria these radicals cause oxidative damage to the capillary endothelium, and in addition these structures [and probably adjacent lymphatic capillaries as well] are compressed and collapsed by the continuing cellular influx. These events, probably coupled with local neutrophil death and degranulation [DG], create tiny foci of initial necrosis [visible in the lungs of guinea pigs by 5–7 days].

Fig.3

As cells die in the initial focus of infection, the lesion now is starting to take on the appearance of the classical granuloma [A] with a necrotic core and a circular rim of leukocytes. The small areas of necrosis have now coalesced forming a central structure around which macrophages and the first incoming sensitized lymphocytes now accumulate and surround in large numbers. Some bacteria are probably killed at this point, but others are released by dying macrophages and thus become extracellular. The bacilli physiologically adapt to survive in the necrosis by forming biofilm-like clusters or communities [NECs]. In humans it is thought these necrotic lesions erode into larger airways creating cavities; this does not happen often in the guinea pig model but it can be observed when the isolate is highly virulent [as, unfortunately, our recent studies looking at Beijing and other strains suggest many of them are]. At this time the surviving persisting bacilli abandon planktonic growth [so they cannot be detected by CFU determinations] and undergo major adaptations, which probably includes cell wall modifications making them very hard or impossible to see by acid fast staining. Also at this time the lesion shows substantial dystrophic calcification [the leading edge of which is depicted here as a black bar], physically isolating the remaining NECs in the residual necrosis between this structure and the intact cellular layer of the granuloma [panel B].

Fig.4

At this point the surviving bacteria are in residual necrosis not that distant from airspaces and capillaries. As the lesions “heal” and calcify and fibrotic tissue is reabsorbed the residual necrosis becomes substantially compressed by the central calcification [A]. Somehow, the NECs are able to sense this -- perhaps the increasing local oxygen tension -- and are pushed towards the liquid [necrosis] air [airspace or capillary] interface, perhaps forming some type of “in vivo pellicle” [B].

Fig.5

Initiation of attempted reactivation. Here, compression of NECs towards airway epithelium generates inflammatory signals, and macrophages arrive [A]. One outcome here could be that the bacilli are killed [in fact this could be the usual outcome -- this could be happening over and over again given the large number of NECs we can detect, but quickly controlled by T cell immunity], but if the dispersing NEC bacilli establish a foothold and survive then a new infectious lesion is potentially created [panel B], and freed bacilli [singly or in clumps; arrow] are pulled up the airway by exhalation. In fact, this is a likely outcome if the T cell response is destroyed by HIV infection.