Insights into signalling and crosstalk in two-component signalling systems of Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), has very recently reclaimed the position of the leading cause of deaths in humans from a single infection agent. This suggests a dire need to design new strategies of intervention. The success of the pathogen primarily is due to mutations against frontline drugs and its ability to stay latent and non-responsive to drugs and immune pressures and get reactivated when the host immune system gets compromised. The ability to develop mutations against drugs is an adaptive response and Mtb thrives in the host owing to its ability of sensing and mounting adaptive responses. To do so, Mtb, like other prokaryotes utilises two-component signalling systems (TCSs). A TCS typically consists of a transmembrane sensor histidine kinase (HK) and a response regulator (RR) which are often genetically located as a cognate pair in an operon. Upon stimulation, the HK gets autophosphorylated and then transfers the phosphate to RR. The phosphorylated RR, generally owing to its increased DNA binding propensity, orchestrates the adaptive response by triggering the transcriptional upregulation of target genes. The phosphorylated RR has a propensity to bind to its own promoter leading to upregulation of the HK and RR. Mtb has 12 TCSs and 4 orphan RRs encoded in its genome. The work reinforces the presence of an alternative paradigm to specificity, i.e., the presence of crosstalk and provides multiple pieces of evidence of various modes of crosstalk in-vivo. It also provides the extent of redundancy in Mtb TCSs, the kinetically feasible cascades arising from the crosstalk landscape and suggests the evolutionary advantages imparted to the pathogen due to crosstalk. All the above information can be potentially used identify critical TCS nodes which can be targeted simultaneously, and the quantum of inhibition evaluated by HTA and our mathematical model, accelerating TB drug discovery