Multiple input–multiple output (MIMO) designs in two-component signalling systems of <i>Mycobacterium tuberculosis</i>

Two-component systems (TCSs), the primary communication pathways in bacteria, are comprised of two proteins: a signal-sensing histidine kinase (HK) and an output-generating response regulator (RR). Classically, individual TCSs have been viewed as simple input-output systems, in which signal propagate via phosphorylation from the HK to the cognate RR, the latter triggering downstream functions. Emerging evidence suggests that TCSs can also operate through intricate networks, collectively sensing multiple inputs and generating fine-tuned, concerted, diversified, and complex outputs, modulated by several factors such as TCS-dependent cross-talk, additional layers of posttranslational modifications, external protein-based signalling input or adaptor molecules, and small RNAs. In this review, using evidence from mycobacterial TCSs, we discuss how TCSs can function as multiple input-multiple output (MIMO) hubs, thereby serving as signal integration and dispersion units to generate complex adaptive responses tuned by many modulating factors. We also discuss how the MIMO landscape of TCSs drives bacterial adaptation and presents potential strategies for therapeutic intervention.