What a Dinner Party! Mechanisms and Functions of Interkingdom Signaling in Host-Pathogen Associations

Abstract

Chemical signaling between cells is an effective way to coordinate behavior within a community. Although cell-to-cell signaling has mostly been studied in single species, it is now appreciated that the sensing of chemical signals across kingdoms can be an important regulator of nutrient acquisition, virulence, and host defense. In this review, we focus on the role of interkingdom signaling in the interactions that occur between bacterial pathogens and their mammalian hosts. We discuss the quorum-sensing (QS) systems and other mechanisms used by these bacteria to sense, respond to, and modulate host signals that include hormones, immune factors, and nutrients. We also describe cross talk between these signaling pathways and strategies used by the host to interfere with bacterial signaling, highlighting the complex bidirectional signaling networks that are established across kingdoms.

FIG 1

Bacterial receptors of mammalian hormones. The host hormones adrenaline (A) and NA are sensed by the membrane-bound bacterial histidine kinases QseC and QseE. QseC also senses the bacterial signal AI-3, while QseE senses sources of SO₄ and PO₄. QseC and QseE phosphorylate KdpE, QseB, and/or QseF (as indicated), and this signaling activates the expression of the T3SS, motility, and Shiga toxin. The stress signal dynorphin has been reported to enter bacterial cells, and its signaling involves the MvfR/PqsR receptor, although it is not clear if MvfR/PqsR directly senses dynorphin. Dynorphyn activates QS and virulence. The estrogen hormones (estrone, estriol, and estradiol) are lipid molecules that enter bacterial cells and influence LuxR-type QS signals, although LuxR-type regulators are great candidates to sense these steroid hormones, there is no evidence that this is the receptor for them. Estrogen hormones inhibit QS. Natriuretic peptides promote virulence, biofilm formation, and LPS modifications; their bacterial receptor is unknown.

FIG 2

Cross signaling with host defenses. (A) The inner membrane (IM)-bound PhoQ histidine kinase from S. enterica directly binds to and responds to mammalian CAMPs and activates the T3SS and LPS modifications and promotes invasion of epithelial cells and intramacrophage replication. The outer membrane (OM) protein OpfR of P. aeruginosa interacts with the cytokine IFN-γ. This signaling promotes QS, induces lectin PA1 expression that causes intestinal damage, and induces pyocyanin expression. (B) The bacterial QS signals, AHLs, cross the mammalian plasma membrane and interact with the PPAR family of nuclear receptors to modulate NF-κB activity and the expression of different ILs. However, not all AHL signaling activity within mammalian cells occurs through PPARs, suggesting that other receptors exist. Additionally, mammalian PON lactonases degrade the AHL signals.

FIG 3

EA sensing and regulation of the eut operon. (A, B) Regulatory proteins are green, and RNA regulatory elements are blue. (A) In S. Typhimurium and EHEC, the eut locus contains 17 genes, including eutR, which encodes the transcription factor EutR. (B) In the absence of EA and vitamin B₁₂, EutR binds the eut promoter but cannot activate transcription. (C) EutR senses EA and vitamin B₁₂ to activate transcription. (D) Schematic of the eut operon in E. faecalis and L. monocytogenes. (E) The sensor kinase EutW autophosphorylates in response to EA and then transfers this phosphate to the RR EutV. In the absence of vitamin B₁₂, the small RNA Rli55/EutX interacts with and sequesters EutV. (F) Vitamin B₁₂ binds the Rli55/EutX mRNA and causes a conformational change that results in premature transcription termination, thereby enabling phosphorylated EutV to bind to and relieve transcriptional repression of the eut locus.

FIG 4

Sugar regulation at the interfaces among the host, microbiota, and enteric pathogens. (A) EHEC senses fucose cleaved from the mucus layer by B. thetaiotaomicron (B. theta) in the colon as a cue to recognize that it is in the intestinal lumen. Fucose is sensed by the histidine kinase FusK in EHEC to rewire transcription, repressing the expression of the LEE and fucose utilization genes to adapt to this intestinal compartment. (B) As disease progresses, EHEC produces mucinases that obliterate the mucus layer. EHEC gains access to the epithelium, as do B. thetaiotaomicron and other members of the microbiota. (C) However, without mucus as a carbon source, this is a carbon-poor environment where B. thetaiotaomicron starts to secrete succinate, which, upon being taken up by EHEC, is sensed by the Cra transcription factor as a clue to a gluconeogenic environment. Cra binds to another transcription factor, KdpE, which is an RR phosphorylated by the QseC adrenergic sensor, to integrate adrenergic and sugar sensing to activate virulence gene expression at the interface with the intestinal epithelium. QseC then also, through another RR, QseB, represses the expression of the fusKR genes, further derepressing the LEE (virulence genes).