An evolutionary paradigm favoring crosstalk between bacterial two-component signaling systems

The prevalent paradigm governing bacterial two-component signaling systems (TCSs) is specificity, wherein the histidine kinase (HK) of a TCS exclusively activates its cognate response regulator (RR). Crosstalk, where HKs activate noncognate RRs, is considered evolutionarily disadvantageous because it can compromise adaptive responses by leaking signals. Yet, crosstalk is observed in several bacteria. Here, to resolve this paradox, we propose an alternative paradigm where crosstalk can be advantageous. We envisioned programmed environments, wherein signals appear in predefined sequences. In such environments, crosstalk that primes bacteria to upcoming signals may improve adaptive responses and confer evolutionary benefits. To test this hypothesis, we employed mathematical modeling of TCS signaling networks and stochastic evolutionary dynamics simulations. We considered the comprehensive set of bacterial phenotypes, comprising thousands of distinct crosstalk patterns, competing in varied signaling environments. Our simulations predicted that in programmed environments phenotypes with crosstalk facilitating priming would outcompete phenotypes without crosstalk. In environments where signals appear randomly, bacteria without crosstalk would dominate, explaining the specificity widely seen. Additionally, a testable prediction was that the phenotypes selected in programmed environments would display one-way crosstalk, ensuring priming to future signals. Interestingly, the crosstalk networks we deduced from available data on TCSs of Mycobacterium tuberculosis all displayed one-way crosstalk, offering strong support to our predictions. Our study thus identifies potential evolutionary underpinnings of crosstalk in bacterial TCSs, suggests a reconciliation of specificity and crosstalk, makes testable predictions of the nature of crosstalk patterns selected, and has implications for understanding bacterial adaptation and the response to interventions. IMPORTANCEBacteria use two-component signaling systems (TCSs) to sense and respond to environmental changes. The prevalent paradigm governing TCSs is specificity, where signal flow through TCSs is insulated; leakage to other TCSs is considered evolutionarily disadvantageous. Yet, crosstalk between TCSs is observed in many bacteria. Here, we present a potential resolution of this paradox. We envision programmed environments, wherein stimuli appear in predefined sequences. Crosstalk that primes bacteria to upcoming stimuli could then confer evolutionary benefits. We demonstrate this benefit using mathematical modeling and evolutionary simulations. Interestingly, we found signatures of predicted crosstalk patterns in Mycobacterium tuberculosis. Furthermore, specificity was selected in environments where stimuli occurred randomly, thus reconciling specificity and crosstalk. Implications follow for understanding bacterial evolution and for interventions.