Adaptation to environmental stimuli within the host: two-component signal transduction systems of Mycobacterium tuberculosis

Abstract

Pathogenic microorganisms encounter a variety of environmental stresses following infection of their respective hosts. Mycobacterium tuberculosis, the etiological agent of tuberculosis, is an unusual bacterial pathogen in that it is able to establish lifelong infections in individuals within granulomatous lesions that are formed following a productive immune response. Adaptation to this highly dynamic environment is thought to be mediated primarily through transcriptional reprogramming initiated in response to recognition of stimuli, including low-oxygen tension, nutrient depletion, reactive oxygen and nitrogen species, altered pH, toxic lipid moieties, cell wall/cell membrane-perturbing agents, and other environmental cues. To survive continued exposure to these potentially adverse factors, M. tuberculosis encodes a variety of regulatory factors, including 11 complete two-component signal transduction systems (TCSSs) and several orphaned response regulators (RRs) and sensor kinases (SKs). This report reviews our current knowledge of the TCSSs present in M. tuberculosis. In particular, we discuss the biochemical and functional characteristics of individual RRs and SKs, the environmental stimuli regulating their activation, the regulons controlled by the various TCSSs, and the known or postulated role(s) of individual TCSSs in the context of M. tuberculosis physiology and/or pathogenesis.

Fig. 1.

Organization of the prototypical TCSS and phosphorelay systems in bacteria. (A) The prototypical TCSS is comprised of a single sensor kinase (SK) and a single response regulator (RR). The input domain of the SK recognizes a specific signal(s) from the environment. This recognition results in activation of the kinase domain and autophosphorylation in the output domain of the SK at a conserved histidine residue. The output domain of the phosphorylated SK interacts with the receiver domain of the RR, catalyzing the transfer of phosphate to a conserved aspartate residue within the receiver domain. Phosphorylation of the RR activates its output domain, resulting in conformational changes in the RR that help mediate specific biological activities, including DNA binding and transcriptional regulation. (B) Phosphorelay systems are comprised of an SK and a terminal RR. These systems also contain an intermediate regulator (connector) lacking an output domain and a phosphotransfer protein with a conserved histidine for phosphorylation. In some phosphorelays, the intermediate phosphotransfer protein and the SK are fused. (Modified from reference with permission of the publisher.)