An Evolutionary Paradigm Favoring Cross Talk 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). Cross talk, where HKs activate noncognate RRs, is considered evolutionarily disadvantageous because it can compromise adaptive responses by leaking signals. Yet cross talk is observed in several bacteria. Here, to resolve this paradox, we propose an alternative paradigm where cross talk can be advantageous. We envisioned programmed environments, wherein signals appear in predefined sequences. In such environments, cross talk 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 cross talk patterns competing in varied signaling environments. Our simulations predicted that in programmed environments phenotypes with cross talk facilitating priming would outcompete phenotypes without cross talk. In environments where signals appear randomly, bacteria without cross talk would dominate, explaining the specificity widely seen. Additionally, a testable prediction was that the phenotypes selected in programmed environments would display one-way cross talk, ensuring priming to future signals. Interestingly, the cross talk networks we deduced from available data on TCSs of Mycobacterium tuberculosis all displayed one-way cross talk, which was consistent with our predictions. Our study thus identifies potential evolutionary underpinnings of cross talk in bacterial TCSs, suggests a reconciliation of specificity and cross talk, makes testable predictions of the nature of cross talk patterns selected, and has implications for understanding bacterial adaptation and the response to interventions.