Penitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of view

Abstract

SummaryGranuloma formation represents a pivotal point during human infection with Mycobacterium tuberculosis, for this structure may limit mycobacterial spread and prevent active disease, while at the same time allow for the survival and persistence of viable mycobacteria within the host. The current therapeutic regimens for treating tuberculosis disease have proven effective in developing countries. However, in countries with large populations, limited access to health care, and high incidence of HIV co-infection, tuberculosis disease continues to represent a major global health emergency. Particularly, the emergence of extensively and multidrug-resistant forms of tuberculosis underscores the need develop new treatment strategies. Recent mechanistic studies have identified bacterial virulence mechanisms that subvert host responses and lead to an inappropriate upregulation of host factors such as tumour necrosis factor-a (TNF-a) and matrix metalloproteinases (MMPs). Paradoxically, then, part of the mycobacterial virulence programme may be to promote granuloma development and maturation. These observations suggest that together with appropriate anti-microbials host-based therapeutics directed at TNF-a and MMP inhibition may counteract the microbial subterfuge, reduce the pro-granulomatous response, and offer an enhanced therapeutic effect. Hostdirected therapy that alters the immune response may offer an alternative approach towards reducing treatment duration, the risk of anti-microbial resistance and improving patient outcome.

Pulmonary Mycobacterial Granuloma

“…Given that many mycobacterial species are notoriously difficult to eliminate, our current findings provide a plausible mechanism to explain why mycobacterial infections such as M.tb can remain latent for a lifetime in the lung of otherwise healthy, immune-competent human beings. [7][8][9] It is noteworthy that we used an attenuated strain of mycobacteria (M. bovis BCG), but not virulent M.tb, in our current study. The current physical and technical constrains in our level III biohazard containment facility does not allow us to carry out the elaborate procedures needed for isolating bronchoalveolar and granuloma cells from M.tb-infected lungs.…”

“…4 -6 After mycobacterial infection in the lung, the host attempts to control the infection by locally segregating the bacteria in a granuloma formed under type 1 immune conditions. [7][8][9][10] Granuloma formation is thus the pathological hallmark of pulmonary mycobacterial infection readily detectible on a radiographical image. The granuloma is an organized collection of inflammatory and immune cells primarily composed of infected macrophages, recruited dendritic cells, and activated lymphocytes.…”

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

“…Granulomas develop in tuberculosis (TB), leprosy, schistosomiasis, and leishmaniasis and function to contain and sometimes destroy the etiologic agent (1)(2)(3). The precise role of granulomas in protection against TB remains elusive (1,(4)(5)(6). Although Mycobacterium tuberculosis (Mtb)-infected macrophages within granulomas are endowed with antimycobacterial defenses induced by the action of T cells, the long-term persistence of Mtb in the face of strong immune responses suggests that these mechanisms could be both evaded and harnessed by Mtb or that they function inefficiently in the granuloma environment (5,(7)(8)(9).…”

Mycobacterial TDM: A Coat to Modulate Post Primary Pathogenesis?

“…On the other hand, TDM has unique properties allowing focused innate inflammatory responses to initiate a protective granulomatous response. We can now hope to add additional layers of complexity through [1] investigation of its function in regulating adaptive events in immune competent hosts, and, through [2] further understanding of physical interactions with host lipids to generate toxic cues related to development of cavitation and necrosis in post primary tuberculosis. …”

“…The characteristic histopathology associated with clinical primary tuberculosis manifests as a granulomatous lesion comprised of activated epithelioid macrophages cuffed by "ring-leader" lymphocytes [1,2]. The process allows functional sequestration of organisms with described (limited) focal inflammation, in essence providing a mechanism whereby hosts may carry the disease for later spread to other individuals.…”