Review Article Journal of Innate J Innate Immun 2019;11:263–279 Received: May 16, 2018 DOI: 10.1159/000494069 Accepted after revision: September 24, 2018 Immunity Published online: November 14, 2018 Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of Pseudomonas aeruginosa Infections Maria V. Turkina Elena Vikström Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden Keywords Introduction Host-pathogen interactions · Bacteria · Cell-to-cell signaling · Quorum sensing · Pseudomonas aeruginosa · N-acyl Quorum sensing (QS) is a cell-to-cell communication homoserine lactones · Biofilms · Innate immunity · Mucosal that allows bacteria to recognize the population density surfaces · Proteogenomics by producing and sensing small diffusible signaling mol- ecules. This form of bacterial intercellular signaling coor- dinates gene regulation and controls numerous coopera- Abstract tive behaviors, including biofilm formation, virulence Cell-to-cell signaling via small molecules is an essential pro- traits, metabolic demands, and host-microbe interactions cess to coordinate behavior in single species within a com- [1]. Multicellular eukaryotic organisms have coexisted munity, and also across kingdoms. In this review, we discuss with bacteria for approximately 2 billion years under evo- the quorum sensing (QS) systems used by the opportunistic lutionary pressure and both represent remarkable exam- pathogen Pseudomonas aeruginosa to sense bacterial popu- ples of adaptive evolution. Our body meets numerous po- lation density and fitness, and regulate virulence, biofilm de- tential pathogens daily, and during the first critical hours velopment, metabolite acquisition, and mammalian host de- and days, the outcome of infections and development of fense. We also focus on the role of N-acylhomoserine lactone- disease depend on the properties of both bacterial com- dependent QS signaling in the modulation of innate immune munity and our innate immune system [2]. Epithelial sur- responses connected together via calcium signaling, homeo- face linings of the mucosa, e.g., in the gut and lung, pro- stasis, mitochondrial and cytoskeletal dynamics, and govern- vide physical and immune barriers between the host and ing transcriptional and proteomic responses of host cells. A pathogens and external environment. Tight junctions future perspective emphasizes the need for multidisciplinary (TJ) and adherens junctions (AJ) are specialized trans- efforts to bring current knowledge of QS into a more detailed membrane protein complexes located between neighbor- understanding of the communication between bacteria and ing epithelial cells and associated with the cytoskeleton host, as well as into strategies to prevent and treat P. aerugi- and regulatory proteins [3]. The apical surface of the epi- nosa infections and reduce the rate of antibiotic resistance. thelial cells in the intestine and lung is equipped with two © 2018 The Author(s) types of projections, microvilli versus cilia, and covered Published by S. Karger AG, Basel © 2018 The Author(s) Dr. Elena Vikström Published by S. Karger AG, Basel Department of Clinical and Experimental Medicine Linköping University Faculty of Health Sciences E-Mail [email protected] This article is licensed under the Creative Commons Attribution- SE–58185 Linköping (Sweden) www.karger.com/jin NonCommercial-NoDerivatives 4.0 International License (CC BY- NC-ND) (http://www.karger.com/Services/OpenAccessLicense). E-Mail elena.vikstrom @ liu.se Usage and distribution for commercial purposes as well as any dis- tribution of modified material requires written permission. with a mucus layer made of glycoproteins that protects QS Signaling Networks in P. aeruginosa against mechanical, chemical, and microbial agents. The lumen of the gut and the lung is also largely inhospitable Concept of QS for microbes because of the presence of antimicrobial fac- The general concept of QS is that small-signal mole- tors, such as lysozyme, α-defensin, and lactoferrin. More- cules broadcast the information about cell density in the over, macrophages and neutrophils are activated by bac- bacterial population and allow collective coordinated terial products (e.g., cell wall components, formylated production of costly extracellular items. This gives ben- peptides, flagellin) or immune stimuli (e.g., complement eficial cooperation with each other, behavior as a power- components, cytokines, antibodies) can quickly phago- ful multicellular community, and performance of tasks, cyte and kill bacterial pathogens at the early onset of in- which would be impossible for single cells [1]. Sophisti- fection, and dendritic cells in mucosa activate the adap- cated QS networks exist in both Gram-negative and tive immune response, including T and B cells [3]. Using Gram-positive bacteria, and they communicate via many QS communication, bacteria can coordinate their social different circuits and various signal molecules. Despite behavior, influencing host cell activities in a noninvasive the diversity of QS mechanisms, there are common items manner. The early events in the communication between among these networks. Many of the QS-controlled social bacteria and host cells may happen even before the bac- factors and cooperative behaviors are conserved and in- teria bind to and enter host cells and then spread further. clude biofilm formation, virulence traits, and metabolic Research over the past 2 decades has greatly increased our demands [6]. understanding of how bacterial QS communication or- chestrate cooperative behaviors of bacteria during host- P. aeruginosa QS Systems microbe interactive coexistence. These advances open up P. aeruginosa harbors one of the most complex QS sys- new frontiers of the sociomicrobiology research field tems (Fig. 1), equipped with at least four distinct but aiming to find new strategies for the prevention and treat- deeply intertwined and subordinated circuits [6]. There ment of bacterial infections. are two N-acylhomoserine lactone (AHL) circuits, LasI/ LasR and RhlI/RhlR; both are homologs of LuxI/LuxR type, and both are activated by an increased cell density Pseudomonas aeruginosa within a bacterial population (Fig. 1). Each AHL-depen- dent system is composed of a LuxI-type synthase and a Pseudomonas aeruginosa is a social, nonfermentative LuxR-type receptor [6]. LasI produces a molecule, N- opportunistic Gram-negative bacterium that inhabits 3-oxo-dodecanoyl-L-homoserine lactone (3O-C12-HSL), diverse environments. Normally considered to be com- which is detected by the cytoplasmic receptor LasR. RhlI mensals on the host body, bacteria can establish them- produces N-butyryl-L-homoserine lactone (C4-HSL), selves as opportunistic pathogens. Being highly adapt- which is recognized by the cytoplasmic receptor RhlR. able, invasive, toxigenic, and able to colonize various LasR and RhlR are transcriptional regulators and togeth- surfaces and tissues, P. aeruginosa can cause severe noso- er control the activation of more than 300 genes in the P. comial outbreaks and also threaten local and systemic in- aeruginosa genome [7]. In addition, there is a 3O-C12- fections in patients with compromised underlying health HSL-binding receptor QscR, a LuxR homolog which not conditions, particularly in those with ventilator-associat- only controls its own set of genes but also inactivates LasR ed pneumonia, burn wounds, cystic fibrosis, and blood- and RhlR and thereby represses many Las- and Rhl-de- stream infections [4]. As other members in a large group pendent genes resulting in prevention of QS responses of so-called ESKAPE pathogens (Enterococcus faecium, before the bacteria reach a quorum in a population [8]. Staphylococcus aureus, Klebsiella pneumonia, Acineto- An additional level of complexity is added by the third bacter baumannii, Pseudomonas aeruginosa, and Entero- QS circuit, the P. aeruginosa quinolone signal (PQS) sys- bacter species), it is capable of escaping from the action of tem (Fig. 1), which is interconnected to the AHL-depen- multiple drugs and represents a new paradigm of a “su- dent signaling and can be triggered by iron limitation perbug” in pathogenesis, transmission, and antibiotic re- within bacterial population [9]. Here, PqsABCDE pro- sistance [5]. Therefore, traditional therapeutic options duces the precursor 2-heptyl-4-quinolone (HHQ), and for P. aeruginosa have become limited and finding novel PqsH catalyzes conversion of HHQ to 2-heptyl-3-hy- alternative prevention and treatment strategies is an ur- droxy-4-quinolone (PQS), detected by the receptor PqsR gent priority. [10]. Phosphate starvation can activate the production of 264 J Innate Immun 2019;11:263–279 Turkina/Vikström DOI: 10.1159/000494069 Fig. 1. The QS system in P. aeruginosa. The scheme illustrates (in different colors) four main circuits of the QS system: AHL-dependent circuits, Las and Rhl, which are interconnected to the PQS circuit, and IQS. They can be triggered by certain stimuli, such as bacterial cell density or iron limitation, etc. Chemical structures are shown for four main QS signal molecules, 3-O-C12-HSL, C4-HSL, PQS, and IQS. Furthermore, the scheme shows QS- regulated products and cooperative behaviors. Quorum Sensing Crosstalk J Innate Immun 2019;11:263–279 265 DOI: 10.1159/000494069 Fig. 2. QS communication during host-microbe interaction. The scheme illustrates the impact of P. aeruginosa 3O-C12-HSL on the mammalian host at cellular and molecular