Molecular Crosstalk between Bacterial Two-Component Regulatory Systems and Host Immune Modulation: Implications for Antimicrobial Resistance and Pathogenic Persistence

Abstract

Bacterial two-component systems (TCSs) are versatile regulatory circuits that enable pathogens to sense environmental and host-derived signals and translate them into adaptive genetic responses. These systems, typically composed of a sensor histidine kinase and a response regulator, play pivotal roles in controlling virulence, antimicrobial resistance, and persistence. In parallel, the host immune system employs innate and adaptive mechanisms to recognize and eliminate pathogens. However, a dynamic molecular crosstalk exists, wherein TCSs detect immune-derived cues such as antimicrobial peptides, oxidative stress, and ion limitation, and in turn, modulate bacterial physiology to evade or manipulate host defenses.

Well-studied examples—including PhoPQ, PmrAB, CsrRS, and Agr systems—highlight how TCSs govern immune evasion, biofilm formation, and resistance to last-resort antibiotics such as polymyxins and vancomycin. These processes contribute significantly to chronic infections and treatment failures. Targeting TCSs has therefore emerged as a promising therapeutic strategy. Experimental inhibitors of histidine kinases and response regulators demonstrate potential to attenuate bacterial virulence without exerting strong selective pressure for resistance. Moreover, combining TCS-targeting compounds with conventional antibiotics may enhance treatment efficacy.

This review synthesizes current knowledge of TCS-immune interactions, emphasizes their contribution to antimicrobial resistance and persistence, and explores therapeutic perspectives. Understanding this molecular dialogue provides crucial insights into host-pathogen interactions and offers new opportunities for combating multidrug-resistant infections in the post-antibiotic era.

Keywords:

Two-Component Regulatory Systems (TCSs), Host–Pathogen Interactions, Antimicrobial Resistance (AMR), Immune Modulation, Virulence Regulation, Pathogenic Persistence

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