Immunological roulette: Luck or something more? Considering the connections between host and environment in TB

Abstract

Accurate prediction of which patient will progress from a sub-clinical Mycobacterium tuberculosis infection to active tuberculosis represents an elusive, yet critical, clinical research objective. From the individual perspective, progression can be considered to be the product of a series of unfortunate events or even a run of bad luck. Here, we identify the subtle physiological relationships that can influence the odds of progression to active TB and how this progression may reflect directed dysbiosis in a number of interrelated systems. Most infected individuals who progress to disease have apparently good immune responses, but these responses are, at times, compromised by either local or systemic environmental factors. Obvious disease promoting processes, such as tissue-damaging granulomata, usually manifest in the lung, but illness is systemic. This apparent dichotomy between local and systemic reflects a clear need to define the factors that promote progression to active disease within the context of the body as a physiological whole. We discuss aspects of the host environment that can impact expression of immunity, including the microbiome, glucocorticoid-mediated regulation, catecholamines and interaction between the gut, liver and lung. We suggest the importance of integrating precision medicine into our analyses of experimental outcomes such that apparently conflicting results are not contentious, but rather reflect the impact of these subtle relationships with our environment and microbiota.

Balance between Protection and Pathogenic Response to Aerosol Challenge with Mycobacterium tuberculosis (Mtb) in Mice Vaccinated with TriFu64, a Fusion Consisting of Three Mtb Antigens

“…Protection against disease upon infection with Mtb is not simply a result of reduced bacterial burden; indeed, the immune response and vaccine-induced protection are not often associated with clearance of Mtb from the host. The ability to resist TB disease is a combination of a series of linked physiological parameters [ 12 ]. Before investigating ways in which to improve the TriFu64 triple-antigen fusion as a vaccine, we wanted to assess the impact of the vaccination on mouse health.…”

“…While we have a high level of understanding of what constitutes the immune response to Mtb, we are not clear which elements of the immune response contribute to protection and which contribute to pathogenic outcomes. We have proposed that, while TB is predominantly a lung disease, it is by addressing the body as a whole that we will gain an understanding of the factors which promote active disease in those that are infected but in whom the disease is latent (latent TB infection—LTBI) [ 12 ]. While experimental medicine can provide insight into which clinical parameters are associated with poorer outcomes for the patient, we need to use animal models to investigate potential mechanistic mediators of both protection and pathology [ 13 ].…”

Mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation

“…2 Additionally, as an intracellular pathogen, Mtb has developed multiple strategies to regulate host cellular functions to better survive in the hostile environment of host cells. [3][4][5][6][7] Therefore, a better understanding of the molecular mechanisms underlying the interactions between Mtb and host cells is crucial for identifying novel targets for the development of TB treatments.…”