Date Published: February 4, 2019
Publisher: Public Library of Science
Author(s): Nathan J. MacGilvary, Yuzo L. Kevorkian, Shumin Tan, Helena Ingrid Boshoff.
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.
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 [1–7], and successful host colonization thus 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. For Mycobacterium tuberculosis (Mtb), pH ([H+] flux) is well-established as a critical signal during host colonization [8, 9], with the bacteria concurrently able to robustly maintain intrabacterial pH . We have since identified chloride (Cl-) as an ionic cue important for Mtb , but it remains an open question what other abundant ions may flux during Mtb colonization, and how bacterial ionic homeostasis may affect response to environmental ionic cues. Mtb is a bacterium of immense public health importance, being the leading cause of death from infectious diseases worldwide . 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.