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Molecular and Cellular Microbiology (MCM) | Host-Microbe Interaction and Pathogenesis
Microbiol. Biotechnol. Lett. 2022; 50(1): 1-14
Poonam Kanojiya, Rajashri Banerji, and Sunil D. Saroj*
Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune-412115, Maharashtra, India
Correspondence to :
Sunil D. Saroj, email@example.com
Bacteria communicate with each other through an intricate communication mechanism known as quorum sensing (QS). QS regulates different behavioral aspects in bacteria, such as biofilm formation, sporulation, virulence gene expression, antibiotic production, and bioluminescence. Several different chemical signals and signal detection systems play vital roles in promoting highly efficient intra- and interspecies communication. Gram-negative bacteria coordinate gene regulation through the production of acyl homoserine lactones (AHLs). Gram-positive bacteria do not code for AHL production, while some gram-negative bacteria have an incomplete AHL-QS system. Despite this fact, these microbes can detect AHLs owing to the presence of LuxR solo receptors. Various studies have reported the role of AHLs in interspecies signaling. Moreover, as bacteria live in a polymicrobial community, the production of extracellular compounds to compete for resources is imperative. Thus, AHL-mediated signaling and inhibition are considered to affect virulence in bacteria. In the current review, we focus on the synthesis and regulation mechanisms of AHLs and highlight their role in interspecies bacterial signaling. Exploring interspecies bacterial signaling will further help us understand host-pathogen interactions, thereby contributing to the development of therapeutic strategies intended to target chronic polymicrobial infections.
Keywords: Quorum sensing, interspecies signaling, LuxR solo, virulence, bacterial communication, pathogenesis
Communication between bacteria of different species and genus is facilitated by signaling molecules synthesized by them and receptors present on bacteria. Microbial interactions have been widely studied to gain insight into growth-inhibitory interactions. However, interspecies signaling may result in other events like antibiosis, motility, competence, and symbiosis. In recent years, various studies on microbial interactions gave us a better awareness of the association of microbes to the components of their habitat and other microbes . There has been a significant rise in research over the last few years documenting a wide variety of interspecies signaling molecules and interactions [2, 3]. The identification of any transition in the growth of an organism living in a polymicrobial community may imply the existence of unnoticed compounds utilized to interact with one another. Exploring microbial relationships can thus direct identification of molecules involved in interspecies interaction. Signaling may lead to a modified use of known molecules . Bacteria can regulate their gene expression as a response to fluctuations in cell density. This process of regulating the gene expression is called quorum sensing (QS). The functioning of QS occurs in a sequential manner starting from the synthesis of signal molecules. Bacteria synthesize signal molecules called autoinducers, and their concentration increases with an increase in the cell population. The detection of autoinducers is critical for bacteria. This is done by receptors present on bacteria. Only after achieving a threshold concentration of autoinducers, alteration in gene expression is observed. Gram-positive and gram-negative bacteria respond to chemically distinct signaling molecules. For communication, gram-positive and gram-negative bacteria make use of oligopeptides and acylated homoserine lactone (AHL) as autoinducers, respectively . Most gram-negative bacteria use AHL as intercellular signaling molecules to regulate the QS in response to cell density. These chemical signals are synthesized by the LuxI family of proteins . After exceeding the threshold concentration of AHL, these signaling molecules bind to the LuxR homologs, i.e., the intracellular receptors. Binding of the LuxR to AHL molecules results in a change in gene transcription. It has become increasingly evident over the past few years that this is a very simplistic view of AHL-dependent QS, and that there is, in fact, considerable variation in the way LuxI-R homologs function . To understand infections and design strategies to evade the infections, understanding the communication between microbes in mixed infection is of concern. Taking into consideration that AHLs play a significant role in interspecies communication, the current review summarizes the synthesis of AHLs, regulation of AHL QS, and focuses on findings of AHLs in interspecies bacterial signaling which will provide a better understanding of communication amongst microbes and in turn can help in developing intervention strategies.
AHLs are the most thoroughly studied signal molecules in gram-negative bacteria. AHL synthase of the LuxI family synthesizes the signal molecule which is detected with the help of AHL receptors of the LuxR family of transcriptional regulators. The AHL autoinducers only bind to the LuxR-type cognate proteins when they cross a critical concentration. Autoinducer binding regulates the activity of the LuxR protein . A wide range of functions like bioluminescence, biofilm formation, and synthesis of virulence factors are regulated by AHL dependent QS circuits .
AI-2 is a common signal molecule utilized by both gram-positive and gram-negative bacteria. AI-2, which is different from homoserine lactones, requires LuxS for its synthesis . LuxP is a periplasmic protein that acts as a primary receptor of AI-2. LuxP on interaction with AI-2 modulates LuxQ. LuxPQ participates in signaling required for regulation of bioluminescence in
AI-3 is a bacterial signal molecule synthesized by commensals residing in the intestine of the humans. They play a role in virulence as they induce transcription of virulence genes. The detection of epinephrine and norepinephrine by prokaryotes indicates that AI-3 might play a role in communication. A two-component system homologous to PmrAB of
Many of the human and plant pathogens are capable of synthesizing indole and its derivatives [12, 13]. Indole synthesis requires tryptophan as a substrate. Two genes involved in the degradation and transport of tryptophan are
Antibiotics are organic compounds synthesized by bacteria to kill or inhibit other microbes. They bind to a specific site on the target cell to act on them. Microbes synthesize antibiotics as secondary metabolites which gives them a competitive survival advantage. Several studies revealed the property of antibiotics to act as a signaling molecule at sub-inhibitory concentrations [16−20]. Many other molecules act as signaling molecules in bacteria. Autoinducing peptides, diffusible signal factors, and diketopiperazines are few other classes of molecules involved in interspecies signaling . Here we focus on AHLs as a signal molecule for interspecies interaction to gain insights on its role in communication (Table 1).
Autoinducer molecules are synthesized by a wide range of organisms like
An autoinducer molecule like AHL can simply diffuse in a cell and bind reversibly to its specific receptor. Bacteria try to equilibrate the intracellular and extracellular concentration of AHLs; this was confirmed by a study that reported that the diffusion of 3OC6-HSL was strongly influenced by its concentration gradient over the bacterial envelope . AHL molecule does not have to be synthesized by the same bacteria to cross the bacterial envelope. Signal molecules synthesized by one bacterium can travel through the envelope of another by diffusion. Similarly, LuxR-type proteins are not solely activated by endogenous AHLs and can be induced by an external supply of AHLs. The findings support the fact that transport of AHLs is dependent on passive diffusion. The hydrophobicity of the AHLs increases with the number of carbon atoms in the side chain. AHLs having side chains with more than eight carbon atoms thus accumulate in the membrane. Other than the length of the side chain, the degree of substitution also affects the movement of AHL across membrane bilayer. Efflux pumps help in the extrusion of long-chain AHLs as they are not freely permeable. BpeAB-OprB and MexAB-OprD efflux systems are involved in the transport of AHLs. BpeAB-OprB is present in the pathogen
Synthesis of AHLs occurs by the activity of a solo enzyme that belongs to the LuxI family of AHL synthases. SAM and intermediates of fatty acid metabolism act as a precursor molecule for AHL synthesis [27, 31]. AHL synthase acts on substrate molecules and activates a cascade of reactions to synthesize AHLs. In
The concentration of AHLs in the extracellular pool is determined by the presence of the producers (bacteria documented to synthesize and secrete AHLs) and the degraders (bacteria documented to produce AHL degrading enzymes). The AHLs from the extracellular pool can be taken by the producers as well as the nonproducers which can interact with the receptors to generate a response (Fig. 1).
Various studies on virulence and QS have highlighted the need to address the role of AHL QS in bacterial communication . Recent studies have revealed that the genomes of different proteobacteria have sequences of QS-related LuxR AHL sensors/regulators. Numerous proteobacteria lack a cognate LuxI AHL synthase . Many bacteria like
Bacteria can detect and respond to the changes occurring in the environment. QS is one of the mechanisms by which bacteria respond to changes in population density. The presence of multiple QS systems in
The presence of LuxR solos in non-AHL producing bacteria indicates a possibility that AHL producers and non-AHL producers can sense and respond to the signal molecules synthesized by other microbes. In
The wide variety of bacteria that controls the expression of virulence and colonization-relevant traits through QS systems indicates that capable quorum sensor inhibitors have significant potential . To reduce the expression of AHL dependent virulence factors, inhibition of AHL production is of concern. Analogs of SAM act as inhibitors as they block the signal reception. Various substrate analogs like L-Sadenosylcysteine, butyryl-SAM, holo-ACP, sinefungin, and D/L-S-adenosylhomocysteine are evaluated for their inhibitory action on AHL production .
QS often favors conduct that is harmful to other nearby organisms. One of the well-studied examples of this is the activation of virulence genes using AHL mediated QS in
Another approach to inhibit AHLs is the use of enzymes that alter AHLs in such a way that they are not functional anymore. Oxidized halogens react only with AHLs containing a 3-oxo group. AHLs from
Swarming is a type of surface translocation used by many bacteria like
The approaches mentioned above focuses on inhibiting AHL synthesis. But another interesting aspect is the inhibitory effect of AHLs on bacterial growth and virulence. The inhibitory effect of AHLs against
It is now widely accepted that bacteria live in polymicrobial communities and have specific intra and interspecies communication mechanisms. Many signaling mechanisms are established, but it seems certain that several more are still to be identified. The concept of interspecies communication is supported by various studies . AHL-based communication systems have been identified in a number of pathogenic gram-negative bacteria which cause diverse problems, including food poisoning and human lung infections. Monitoring cell to cell communication enables us to explore the efficacy of molecules that restrict communication in biofilm systems as well as other complex instances. As AHLs play a role in interspecies communication in
AHLs serve to control the expression of the bacterial virulence genes via cell-cell contact, but can also be a virulence determinant by virtue of immunomodulatory properties. AHLs are reported to down-regulate host innate immunity . Because AHL mediated QS is essential for the virulence of several bacteria, the signaling molecules and mechanism is the focus for designing of new types of therapies, antipathogenic agents, compounds that cannot kill bacterial pathogens but impair the ability to trigger infections. The challenge here is to identify and test the efficacy of QS inhibitors in the treatment of infections, particularly persistent biofilm infections.
Bacteria exist in polymicrobial community in nature. As a survival strategy bacterium has adapted several characters like sensing nearby bacteria and responding to the metabolites in the vicinity, bacteria are hardly reported in seclusion, and evolution seems to have established a mechanism for sensing changes in the environment, for determining population density of self and other bacteria in mixed-species populations, and for responding to these details by regulating gene expression. AHL mediated QS helps in survival by regulating genes in response to extracellular factors, and, most significantly, compelling evidence indicates that many pathogens depend on AHL QS to facilitate infection. Detailed awareness of intra- and inter-species signaling processes will undoubtedly improve our understanding of host-pathogen relationships. It will also give us insights about the processes underlying infectious diseases and will help develop and implement new therapeutic strategies. Inhibiting the AHL mediated interspecies signaling could be one of the potential targets for development of novel antimicrobials.
PK and RB are supported by the junior research fellowship program of the Symbiosis International (Deemed University).
The work was supported by the Ramalingaswami fellowship program of Department of Biotechnology, India under grant BT/RLF/Reentry/41/2015.
The authors have no financial conflicts of interest to declare.
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