Abstract
Successful host colonization by bacteria requires sensing and response to the local ionic milieu, and coordination of responses with the maintenance of ionic homeostasis in the face of changing conditions. We previously discovered that Mycobacterium tuberculosis (Mtb) responds synergistically to chloride (Cl-) and pH, as cues to the immune status of its host. This raised the intriguing concept of abundant ions as important environmental signals, and we have now uncovered potassium (K+) as an ion that can significantly impact colonization by Mtb. The bacterium has a unique transcriptional response to changes in environmental K+ levels, with both distinct and shared regulatory mechanisms controlling Mtb response to the ionic signals of K+, Cl-, and pH. We demonstrate that intraphagosomal K+ levels increase during macrophage phagosome maturation, and find using a novel fluorescent K+-responsive reporter Mtb strain that K+ is not limiting during macrophage infection. Disruption of Mtb K+ homeostasis by deletion of the Trk K+ uptake system results in dampening of the bacterial response to pH and Cl-, and attenuation in host colonization, both in primary murine bone marrow-derived macrophages and in vivo in a murine model of Mtb infection. Our study reveals how bacterial ionic homeostasis can impact environmental ionic responses, and highlights the important role that abundant ions can play during host colonization by Mtb.
Highlights
Ions are a fundamental component of organisms, playing roles in myriad biological processes.The ionic milieu surrounding a bacterium during infection varies with location and the immune response [1,2,3,4,5,6,7], and successful host colonization requires proper sensing and response to the local ionic milieu, and the ability to coordinate responses with the maintenance of ionic homeostasis in the face of changing conditions
Our study reveals how bacterial ionic homeostasis can impact environmental ionic responses, and highlights the important role that abundant ions can play during host colonization by Mycobacterium tuberculosis (Mtb)
How does Mtb respond transcriptionally to local changes in [K+], and how may this response be linked to the bacterial response to other environmental cues? What is the impact of perturbation of bacterial K+ homeostasis on successful host colonization by Mtb?
Summary
Ions are a fundamental component of organisms, playing roles in myriad biological processes.The ionic milieu surrounding a bacterium during infection varies with location and the immune response [1,2,3,4,5,6,7], and successful host colonization requires proper sensing and response to the local ionic milieu, and the ability to coordinate responses with the maintenance of ionic homeostasis in the face of changing conditions. Uncovering facets of the local environment that the bacteria respond to, and how fundamental aspects of Mtb biology relate to environmental response and colonization success, is critical for comprehension of Mtb-host interactions and has the potential to reveal novel nodes that can be targeted for therapeutic purposes. Our previous discovery of Cl- as a novel environmental signal that Mtb responds to in synergy with pH indicated the significant role that flux and homeostasis of abundant ions can play during Mtb infection and disease [2]. In this context, potassium (K+), the most abundant intracellular cation in both mammalian and bacterial cells, stands out as a compelling candidate for study. How does Mtb respond transcriptionally to local changes in [K+], and how may this response be linked to the bacterial response to other environmental cues? What is the impact of perturbation of bacterial K+ homeostasis on successful host colonization by Mtb?
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