Quorum sensing

Template:More citations needed In biology, quorum sensing or quorum signaling (QS)<ref name="Lupp-et-al-2003" /><ref>Template:Cite journal</ref> is the process of cell-to-cell communication<ref name="Rutherford-2012">Template:Cite journal</ref> that allows bacteria to detect and respond to cell population density by gene regulation, typically as a means of acclimating to environmental disadvantages.<ref name="Postat-2019" />

Quorum sensing is a type of cellular signaling, and can be more specifically considered a type of paracrine signaling. However, it also contains traits of autocrine signaling: a cell produces both an autoinducer molecule and the receptor for the autoinducer.<ref name="Postat-2019">Template:Cite journal</ref> As one example, quorum sensing enables bacteria to restrict the expression of specific genes to the high cell densities at which the resulting phenotypes will be most beneficial, especially for phenotypes that would be ineffective at low cell densities and therefore too energetically costly to express.<ref>Template:Cite journal</ref>

Many species of bacteria use quorum sensing to coordinate gene expression according to the density of their local population. In a similar fashion, some social insects use quorum sensing to determine where to nest. Quorum sensing in pathogenic bacteria activates host immune signaling and prolongs host survival, by limiting the bacterial intake of nutrients, such as tryptophan, which further is converted to serotonin.<ref name="Jugder-2022">Template:Cite journal</ref> As such, quorum sensing allows a commensal interaction between host and pathogenic bacteria.<ref name="Jugder-2022" /> Quorum sensing may also be useful for cancer cell communications.<ref>Template:Cite journal</ref>

In addition to its function in biological systems, quorum sensing has several useful applications for computing and robotics. In general, quorum sensing can function as a decision-making process in any decentralized system in which the components have: (a) a means of assessing the number of other components they interact with and (b) a standard response once a threshold of the number of components is detected. Template:TOC limit

Discovery

The first observations of an autoinducer-controlled phenotype in bacteria were reported in 1970, by Kenneth Nealson, Terry Platt, and J. Woodland Hastings,<ref name="Nealson-et-al-1970">Template:Cite journal</ref> who observed what they described as a conditioning of the medium in which they had grown the bioluminescent marine bacterium Aliivibrio fischeri.<ref name="Bodman-et-al-2003" /> These bacteria did not synthesize luciferase—and therefore did not luminesce—in freshly inoculated culture but only after the bacterial population had increased significantly.

In a series of publications from 1998 to 2001, Bonnie Bassler showed that quorum sensing is not just an isolated mechanism in Aliivibrio fischeri, but is used ubiquitously across bacteria to communicate.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> This advance demonstrated that bacteria are capable of carrying out complex, collective behaviors.<ref>Template:Cite web</ref><ref>Template:Cite web</ref>

Etymology

Because Nealson, Platt, and Hastings attributed the conditioning of the growth medium to the growing population of cells itself, they referred to the phenomenon as autoinduction.<ref name="Nealson-et-al-1970" /><ref name="Nealson-1977" /><ref name="Bodman-et-al-2003" />

In 1994, after study of the phenomenon had expanded into several additional bacteria, Stephen Winans did not believe the word autoinduction fully characterized the true process so, in a review article coauthored with W. Claiborne Fuqua and E. Peter Greenberg,<ref>Template:Cite journal</ref> he introduced the term quorum sensing. Its use also avoided confusion between the terms autoinduction and autoregulation. The new term was not stumbled onto, but rather created through trial and error. Among the alternatives that Winans had created and considered were gridlockins, communiolins, and quoromones.<ref>Template:Cite journal</ref>

Bacteria

Template:Microbial and microbot movement File:Quorum sensing of Gram Negative cell.pdf File:Gram Positive Bacteria Quorum Sensing.pdf

Some of the best-known examples of quorum sensing come from studies of bacteria. Bacteria use quorum sensing to regulate certain phenotype expressions, which in turn, coordinate their behaviors. Some common phenotypes include biofilm formation, virulence factor expression, and motility. Certain bacteria are able to use quorum sensing to regulate bioluminescence, nitrogen fixation and sporulation.<ref name="Pan-2009">Template:Cite journal</ref>

The quorum-sensing function is based on the local density of the bacterial population in the immediate environment.<ref name="Miller Bassler 2001"/> It can occur within a single bacterial species, as well as between diverse species. Both gram-positive and gram-negative bacteria use quorum sensing, but there are some major differences in their mechanisms.<ref name="Bassler-1999a">Template:Cite journal</ref>

Mechanism

For the bacteria to use quorum sensing constitutively, they must possess three abilities: secretion of a signaling molecule, secretion of an autoinducer (to detect the change in concentration of signaling molecules), and regulation of gene transcription as a response.<ref name="Pan-2009" /> This process is highly dependent on the diffusion mechanism of the signaling molecules. QS signaling molecules are usually secreted at a low level by individual bacteria. At low cell density, the molecules may just diffuse away. At high cell density, the local concentration of signaling molecules may exceed its threshold level, and trigger changes in gene expression.<ref name="Bassler-1999a" />

Gram-positive bacteria

Gram-positive bacteria use autoinducing peptides (AIP) as their autoinducers.<ref name="Rutherford-2012" />

When gram-positive bacteria detect high concentration of AIPs in their environment, that happens by way of AIPs binding to a receptor to activate a kinase. The kinase phosphorylates a transcription factor, which regulates gene transcription. This is called a two-component system.

Another possible mechanism is that AIP is transported into the cytosol, and binds directly to a transcription factor to initiate or inhibit transcription.<ref name="Rutherford-2012" />

Gram-negative bacteria

Gram-negative bacteria produce N-acyl homoserine lactones (AHL) as their signaling molecule.<ref name="Rutherford-2012" /> Usually AHLs do not need additional processing, and bind directly to transcription factors to regulate gene expression.<ref name="Bassler-1999a" />

Some gram-negative bacteria may use the two-component system as well.<ref name="Rutherford-2012" />

Examples

Aliivibrio fischeri

The bioluminescent bacterium Aliivibrio fischeri is the first organism in which QS was observed. It lives as a mutualistic symbiont in the photophore (or light-producing organ) of the Hawaiian bobtail squid. When A. fischeri cells are free-living (or planktonic), the autoinducer is at low concentration, and, thus, cells do not show luminescence. However, when the population reaches the threshold in the photophore (about Template:10^ cells/ml), transcription of luciferase is induced, leading to bioluminescence. In A. fischeri, bioluminescence is regulated by AHLs (N-acyl-homoserine lactones) which is a product of the LuxI gene whose transcription is regulated by the LuxR activator. LuxR works only when AHLs binds to the LuxR.

Curvibacter sp.

Curvibacter sp. is a gram-negative curved rod-formed bacterium which is the main colonizer of the epithelial cell surfaces of the early branching metazoan Hydra vulgaris.<ref>Template:Cite web</ref><ref name="Pietschke-2017">Template:Cite journal</ref> Sequencing the complete genome uncovered a circular chromosome (4.37 Mb), a plasmid (16.5 kb), and two operons coding each for an AHL (N-acyl-homoserine lactone) synthase (curI1 and curI2) and an AHL receptor (curR1 and curR2).<ref name="Pietschke-2017" /> Moreover, a study showed that these host associated Curvibacter bacteria produce a broad spectrum of AHL, explaining the presence of those operons.<ref name="Pietschke-2017" /> As mentioned before, AHL are the quorum sensing molecules of gram-negative bacteria, which means Curvibacter has a quorum sensing activity.

Even though their function in host-microbe interaction is largely unknown, Curvibacter quorum-sensing signals are relevant for host-microbe interactions.<ref name="Pietschke-2017" /> Indeed, due to the oxidoreductase activity of Hydra, there is a modification of AHL signalling molecules (3-oxo-homoserine lactone into 3-hydroxy-homoserine lactone) which leads to a different host-microbe interaction. On one hand, a phenotypic switch of the colonizer Curvibacter takes place. The most likely explanation is that the binding of 3-oxo-HSL and 3-hydroxy-HSL causes different conformational changes in the AHL receptors curR1 and curR2. As a result, there is a different DNA-binding motif affinity and thereby different target genes are activated.<ref name="Pietschke-2017" /> On the other hand, this switch modifies its ability to colonize the epithelial cell surfaces of Hydra vulgaris.<ref name="Pietschke-2017" /> Indeed, one explanation is that with a 3-oxo-HSL quorum-sensing signal, there is an up-regulation of flagellar assembly. Yet, flagellin, the main protein component of flagella, can act as an immunomodulator and activate the innate immune response in Hydra. Therefore, bacteria have less chance to evade the immune system and to colonize host tissues.<ref name="Pietschke-2017" /> Another explanation is that 3-hydroxy-HSL induces carbon metabolism and fatty acid degradation genes in Hydra. This allows the bacterial metabolism to adjust itself to the host growth conditions, which is essential for the colonization of the ectodermal mucus layer of Hydrae.<ref name="Pietschke-2017" />

Enterococcus faecalis

Enterococcus faecalis is an opportunistic, gram-positive bacteria that forms biofilm in glass. This process is also known as forming a biofilm in vitro. The presence of (Esp), a certain cell surface protein, aids the formation of a biofilm by E. faecalis.<ref>Template:Cite journal</ref>

The ability of E. faecalis to form biofilms contributes to its capacity to survive in extreme environments, and facilitates its involvement in persistent bacterial infection, particularly in the case of multi-drug resistant strains.<ref name = Schiopu2023>Template:Cite journal</ref> Biofilm formation in E. faecalis is associated with DNA release, and such release has emerged as a fundamental aspect of biofilm formation.<ref name = Schiopu2023/> Conjugative plasmid DNA transfer in E. faecalis is enhanced by the release of peptide sex pheromones.<ref>Template:Cite journal</ref>

Escherichia coli

In the gram-negative bacterium Escherichia coli, cell division may be partially regulated by AI-2-mediated quorum sensing. This species uses AI-2, which is produced and processed by the lsr operon. Part of it encodes an ABC transporter, which imports AI-2 into the cells during the early stationary (latent) phase of growth. AI-2 is then phosphorylated by the LsrK kinase, and the newly produced phospho-AI-2 can be either internalized or used to suppress LsrR, a repressor of the lsr operon (thereby activating the operon). Transcription of the lsr operon is also thought to be inhibited by dihydroxyacetone phosphate (DHAP) through its competitive binding to LsrR. Glyceraldehyde 3-phosphate has also been shown to inhibit the lsr operon through cAMP-CAPK-mediated inhibition. This explains why, when grown with glucose, E. coli will lose the ability to internalize AI-2 (because of catabolite repression). When grown normally, AI-2 presence is transient.

E. coli and Salmonella enterica do not produce AHL signals commonly found in other gram-negative bacteria. However, they have a receptor that detects AHLs from other bacteria and change their gene expression in accordance with the presence of other "quorate" populations of gram-negative bacteria.<ref>Template:Cite journal</ref> AHL quorum sensing regulates a wide range of genes through cell density. Other species of bacteria produce AHLs that Escherichia and Salmonella can detect. E. coli and Salmonella produce a receptor like protein (SdiA) allowing the amino acid sequence that is similar to AHL show AHLs can be found in the bovine rumen and E. coli responds to AHLs taken out of the bovine rumen. Most animals do not have AHL in their gastrointestinal tracts.<ref>Template:Cite journal</ref>

Salmonella enterica

Salmonella encodes a LuxR homolog, SdiA, but does not encode an AHL synthase. SdiA detects AHLs produced by other species of bacteria including Aeromonas hydrophila, Hafnia alvei, and Yersinia enterocolitica.<ref>Template:Cite journal</ref> When AHL is detected, SdiA regulates the rck operon on the Salmonella virulence plasmid (pefI-srgD-srgA-srgB-rck-srgC) and a single gene horizontal acquisition in the chromosome srgE.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Salmonella does not detect AHL when passing through the gastrointestinal tracts of several animal species, suggesting that the normal microbiota does not produce AHLs. However, SdiA does become activated when Salmonella transits through turtles colonized with Aeromonas hydrophila or mice infected with Yersinia enterocolitica.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Therefore, Salmonella appears to use SdiA to detect the AHL production of other pathogens rather than the normal gut flora.

Myxococcus xanthus

Myxococcus is a genus of gram-negative bacterium in the Myxococcacae family. Myxococcus xanthus specifically, a bacillus myxobacteria species within Myxococcae, grows in the upper layers of soil. This bacterium is known for its unique utilization of quorum sensing practices to hunt.

The bacterium uniquely survives not on sugars, but lipids created by the degradation of macromolecules lysed by the species. It hunts and feeds through a density-regulated method of predation that is "the regulation of gene expression in response to cell density."<ref name="Berleman-2009">Template:Cite journal</ref> The pilus propelled microorganism moves with the use of both S- and A- (or gliding) motility, which provide transportation across a dynamic range of different surfaces.<ref>Template:Cite journal</ref> M. xanthusTemplate:'s A-motility is most effective in the presence of a single or low number of cells, allowing the bacteria to glide in high agar concentrations. The S-motility, or social motility, is controlled by the process of quorum sensing and is only effective when cells are within one cell length of a neighbor.<ref>Template:Cite journal</ref> Although the precise specifics of M. xanthusTemplate:'s communication methods for quorum sensing are not well understood, the bacteria mediate the process by using both C-signal and A-factor. The A-factor molecule, produced by M. xanthus, must reach a set concentration to initiate aggregation for hunting.<ref>Template:Cite journal</ref> The C-signal concentration, on the other hand, plays a role in fruiting body production.

The species is known for its ability to use quorum sensing to hunt in special packs with thousands of individual cells, lending to M. xanthusTemplate:'s name "the wolf packs." M. xanthus is inclined to behave in a multicellular fashion. In the presence of many cells, it uses these "wolf packs" to form "highly structured biofilms that include tentacle-like packs of surface-gliding cell groups, synchronized rippling waves of oscillating cells and massive spore-filled aggregates that protrude upwards from the substratum to form fruiting bodies."<ref>Template:Cite journal</ref><ref name="Berleman-2009" /> On the fringes of this film, individual cells can be observed "gliding across the surface, but the majority of cells are observed in large tendril-shaped groups" using S-motility.<ref name="Berleman-2009" />

Staphylococcus aureus

Staphylococcus aureus is a type of pathogen that causes infection to the skin and soft tissue and can lead to a variety of more severe diseases such as osteomyelitis, pneumonia, and endocarditis. S. aureus uses biofilms in order to increase its chances of survival by becoming resistant to antibiotics. Biofilms help S. aureus become up to 1500 times more resistant to antibiofilm agents, which try to break down biofilms formed by S. aureus.<ref>Template:Cite journal</ref>

Streptococcus pneumoniae

Each year Streptococcus pneumoniae kills more than a million people, even though vaccines are available.<ref>Template:Cite journal</ref> A complex quorum sensing system has evolved in S. pneumoniae that regulates bacteriocin production. This system also enables entry into the competent state essential for natural genetic transformation.<ref>Template:Cite journal</ref> In naturally competent S. pneumoniae the competent state is not a constitutive property. However competence can be induced by a peptide pheromone by means of a quorum-sensing mechanism.<ref name = Steinmoen2002>Template:Cite journal</ref> When the competent state is induced, this causes release of DNA from a sub-fraction of the S. pneumoniae population, probably by cell lysis. Then most of the S. pneumoniae cells that have been induced to competence become recipients and take up the DNA released by the donors.<ref name = Steinmoen2002/> Thus it appears that natural transformation in S. pneumoniae is a natural adaptive process for promoting genetic recombination, a process that resembles sexual reproduction in higher organisms.<ref name = Steinmoen2002/>

Pseudomonas aeruginosa

The environmental bacterium and opportunistic pathogen Pseudomonas aeruginosa uses quorum sensing to coordinate the formation of biofilm, swarming motility, exopolysaccharide production, virulence, and cell aggregation.<ref>Template:Cite journal</ref> These bacteria can grow within a host without harming it until they reach a threshold concentration. Then they become aggressive, developing to the point at which their numbers are sufficient to overcome the host's immune system, and form a biofilm, leading to disease within the host as the biofilm is a protective layer encasing the bacterial population.Template:Citation needed The relative ease of growth, handling, and genetic manipulation of P. aeruginosa has lent much research effort to the quorum sensing circuits of this relatively common bacterium. Quorum sensing in P. aeruginosa typically encompasses two complete AHL synthase-receptor circuits, LasI-LasR and RhlI-RhlR, as well as the orphan receptor-regulator QscR, which is also activated by the LasI-generated signal.<ref>Template:Cite journal</ref> Together, the multiple AHL quorum sensing circuits of P. aeruginosa influence regulation of hundreds of genes.

Another form of gene regulation that allows the bacteria to rapidly adapt to surrounding changes is through environmental signaling. Recent studies have discovered that anaerobiosis can significantly impact the major regulatory circuit of quorum sensing. This important link between quorum sensing and anaerobiosis has a significant impact on the production of virulence factors of this organism.<ref>Template:Cite book</ref> There is hope among some humans that the therapeutic enzymatic degradation of the signaling molecules will be possible when treating illness caused by biofilms, and prevent the formation of such biofilms and possibly weaken established biofilms. Disrupting the signaling process in this way is called quorum sensing inhibition.<ref>Template:Cite journal</ref>

Acinetobacter sp.

It has recently been found that Acinetobacter sp. also show quorum sensing activity. This bacterium, an emerging pathogen, produces AHLs.<ref name="biomedcentral">{{cite journal | vauthors = Chan KG, Atkinson S, Mathee K, Sam CK, Chhabra SR, Cámara M, Koh CL, Williams P | display-authors = 6 | title = Characterization of N-acylhomoserine lactone-degrading bacteria associated with the Zingiber officinale (ginger) rhizosphere: co-existence of quorum quenching and quorum sensing in Acinetobacter and Burkholderia | journal = BMC Microbiology | volume = 11 | issue = 1