Genetics and evolution of tuberculosis pathogenesis: New perspectives and approaches

Abstract

Tuberculosis is the most lethal infectious disease globally, but the vast majority of people who are exposed to the primary causative pathogen, Mycobacterium tuberculosis (MTB), do not develop active disease. Most people do, however, show signs of infection that remain throughout their lifetimes. In this review, we develop a framework that describes several possible transitions from pathogen exposure to TB disease and reflect on the genetics studies to address many of these. The evidence strongly supports a human genetic component for both infection and active disease, but many of the existing studies, including some of our own, do not clearly delineate what transition(s) is being explicitly examined. This can make interpretation difficult in terms of why only some people develop active disease. Nonetheless, both linkage peaks and associations with either active disease or latent infection have been identified. For transition to active disease, pathways defined as active TB altered T and B cell signaling in rheumatoid arthritis and T helper cell differentiation are significantly associated. Pathways that affect transition from exposure to infection are less clear-cut, as studies of this phenotype are less common, and a primary response, if it exists, is not yet well defined. Lastly, we discuss the role that interaction between the MTB lineage and human genetics can play in TB disease, especially severity. Severity of TB is at present the only way to study putative co-evolution between MTB and humans as it is impossible in the absence of disease to know the MTB lineage(s) to which an individual has been exposed. In addition, even though severity has been defined in multiple heterogeneous ways, it appears that MTB-human co-evolution may shape pathogenicity. Further analysis of co-evolution, requiring careful analysis of paired samples, may be the best way to completely assess the genetic basis of TB.

Keywords: Genetics of pathogenicity; Host-pathogen co-evolution; Tuberculosis.

Figure 1.. Tuberculosis Disease Progression.

Possible paths from exposure to disease. A: Transition from Exposure to Infection (usually leading to LTBI); B: RSTRs or those who never become infected (a minority of those exposed); C: Development of primary active disease (usually in children or individuals who are immunocompromised, rare or non-existent in others); D: Transition from infection to a state of latency (LTBI, presumably the most common transition post exposure and infection); E: Early clearance of infection, manifested as reversion of TST/QFT; F: Re-activation of disease following a period of latency. Arrow sizes are proportional to likelihood of transition.