Beyond Homeostasis: Potassium and Pathogenesis during Bacterial Infections

Abstract

Potassium is an essential mineral nutrient required by all living cells for normal physiological function. Therefore, maintaining intracellular potassium homeostasis during bacterial infection is a requirement for the survival of both host and pathogen. However, pathogenic bacteria require potassium transport to fulfill nutritional and chemiosmotic requirements, and potassium has been shown to directly modulate virulence gene expression, antimicrobial resistance, and biofilm formation. Host cells also require potassium to maintain fundamental biological processes, such as renal function, muscle contraction, and neuronal transmission; however, potassium flux also contributes to critical immunological and antimicrobial processes, such as cytokine production and inflammasome activation. Here, we review the role and regulation of potassium transport and signaling during infection in both mammalian and bacterial cells and highlight the importance of potassium to the success and survival of each organism.

Keywords: host-pathogen interactions; potassium.

FIG 1

Role of potassium during bacterial infection. (A) Activation of the NLRP3 inflammasome is dependent on two distinct signals. The priming signal is provided by recognition of pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (e.g., toll-like receptors; TLRs) and inflammatory cytokines (e.g., TNF-α and IL-1β). These signals induce MyD88-dependent activation of NF-κB, which promotes the transcription of NLRP3, pro-IL-1β, and pro-IL-18. The activation signal is commonly provided by potassium (K⁺) efflux via P2X7, an ATP-gated cation channel, and the calcium (Ca²⁺)-linked potassium channel K_Ca3.1. Similarly, the insertion and oligomerization of bacterial pore-forming toxins (PFT; e.g., alpha-toxin and listeriolysin O) promotes the efflux of potassium and other small molecules (e.g., ATP) that trigger inflammatory responses. The activation signal promotes the assembly of NLRP3, ASC, and procaspase-1 to form an active NLRP3 inflammasome, leading to the maturation and release of caspase-1, which, in turn, cleaves pro-IL-1β and pro-IL-18 into their mature forms prior to release. Gasdermin D is also cleaved and inserts into the cellular membrane to form a transmembrane pore and induce pyroptosis. Additionally, bacterial flagellin and components of the Gram-negative type three secretion system (T3SS) induce host NLRC4 inflammasome activation (not fully depicted). (B) The Trk, Ktr, and Kdp systems are three of the most common, multicomponent potassium transport systems in bacteria. The Trk system is composed of a transmembrane component (e.g., TrkG/H), cytoplasmic regulatory proteins (e.g., TrkA) that function to cotransport potassium and protons (H⁺), and, in some cases, an ATPase (e.g., SapD). The Ktr system is also multimeric and consists of dimeric transmembrane components (e.g., KtrB/D) and respective octameric cytoplasmic regulatory components (e.g., KtrA/C). The Ktr system is thought to energize potassium uptake via sodium (Na⁺) cotransport. Activity of the Ktr system is often promoted by ATP and inhibited by c-di-AMP binding to the cytoplasmic regulatory component. The inducible Kdp system is transcriptionally regulated by the two-component KdpDE system, where the histidine kinase sensor, KdpD, senses environmental potassium concentration and phosphorylates the transcription factor, KdpE, to activate the expression of kdpFABC. This high-affinity transporter component is composed of a potassium channel (KdpA), ATPase (KdpB), a secondary membrane component thought to mediate affinity (KdpC), and a hydrophobic protein implicated in stabilizing the Kdp complex (KdpF).