By Meryl Liu
In the waters off the coast of Hawaii lives the Hawaiian bobtail squid. A mundane-looking cephalopod hiding in the sand by day, it sets off in the night in its shallow habitat, where the light of the moon and stars pierce through the surface of the water, exposing the nocturnal squid to a multitude of predators. The marine bacterium Vibrio fischeri, living in the surrounding seawater during the day, now begins to migrate into a specialized structure in the squid called the light organ. As the density of bacteria in the light organ becomes greater and greater, the concentration of signaling molecules that each cell releases increases as well. Once a critical population density has been hit, genes (the Lux operon) are induced, and the bacterial cells collectively exhibit bioluminescence, brightening the ventral side of the squid and successfully camouflaging it against the moonlight, hidden from predators.
This symbiotic relationship is thanks to Quorum sensing (QS), a form of intercellular signaling and communication among bacteria that allows them to synchronize and carry out group-coordinated efforts that are not just limited to bioluminescence in the light organs of Hawaiian bobtail squids. Quorum sensing mechanisms are diverse and powerful, consequently playing major roles in the formation of biofilms (resilient and complex communities of microorganisms attached to surfaces), as well as being responsible for many pathogenicity factors that make some bacterial strains so dangerous and infectious. In fact, QS is a vital factor in causing nosocomial, hospital-acquired infections (HAIs) from biofilms formed on contaminated medical equipment.
Vibrio fischeri might not pose any risks of infection to humans, but some of the most well-understood quorum-sensing bacteria do; the most notorious may be Pseudomonas aeruginosa, another Gram-negative, opportunistic pathogen that widely affects immunosuppressed patients in hospitals, such as the elderly, intubated, and those suffering from cystic fibrosis. It’s important to understand, however, that communication through quorum sensing isn’t defined in a conventional, sapient, or conscious sense -- that is, an actual conversation or method of expression. Rather, it is a cell-density dependent mechanism; any one bacterial cell may be producing autoinducer signal molecules on its own, but when these signal molecules reach a certain concentration and are able to transduce signals in many other bacterial cells as well, this triggers gene expression, possibly virulence and pathogenicity, and gives rise for bacterial colonies to operate as if they were a multicellular organism. Quorum sensing networks can range from simple and unidirectional, to complex, layered, and hierarchical systems involving multiple different autoinducers. In P. aeruginosa, at least four interconnected signaling mechanisms are involved that allow it to evade antibiotics, form biofilms, and increase virulence and pathogenicity factors as a social unit.
P. aeruginosa and other Gram-negative bacteria primarily utilize a specific class of autoinducers in quorum sensing known as the acyl-homoserine lactones (AHL), which accumulate both in the cell and in the outside environment. As the bacterial population continues to grow and AHL autoinducer concentration increases until the population reaches a threshold known as a quorum, a threshold concentration of AHL molecules is passed as well. A class of specific receptors, DNA-binding transcription factors known as “R-proteins” (LuxR in Vibrio fischeri and LasR in P. aeruginosa), can recognize and bind to the AHL molecules. These R-proteins then directly regulate the transcription of target genes by binding to or dissociating from certain promoters in prokaryotic operons.
Microorganisms such as P. aeruginosa can attach to a variety of surfaces and develop biofilms, a complex architecture of diverse microflora that is exceptionally resilient to antimicrobial substances as they are enclosed in an extracellular matrix and promote the exchange of genetic material between cells. Biofilms naturally exist on our skin, teeth and in ponds, etc. Quorum sensing, providing bacteria with the ability to communicate and engage in social behaviors, provides substantial advantages in colonizing hosts and surfaces, and high cell densities characteristic of biofilms promotes the spread of plasmids coding for antimicrobial resistance and coordinated biofilm detachment. As P. aeruginosa forms protective biofilms, it is capable of evading host immune responses, developing antibiotic resistance, and, through QS, can coordinate the increased gene expression of virulence determinants in response to immune system attacks. The infection is commonly spread through contaminated surfaces in hospitals, especially after surgeries or implants.
The recognition of quorum sensing as having increasing medical implications is leading to the development of new drug molecules that explore alternatives to traditional bactericidal antimicrobials such as penicillin, which directly attacks the structure of bacterial cells themselves. Novel antimicrobials that inhibit the QS systems of bacteria, disrupting cell to cell communication rather than causing lethality for bacteria, can prove to be more effective as they downregulate the production of virulence factors as well as do away with selective pressures caused by antibiotics that lead to multi-drug resistance in pathogens such as MRSA. Studies have shown that flavonoids have been effective in inhibiting the production of virulence factors in P. aeruginosa.
It is likely possible that in the future, a combination of targeted traditional antimicrobials as well as the integration of novel inhibitor drugs into therapeutic usage will be a key treatment for bacterial infections in the future as the issue of antibiotic resistance continues to become more prominent. In any case, we can thank bioluminescence, Vibrio fischeri, and the Hawaiian bobtail squid for calling our attention to this incredible ability of bacteria: to “talk” amongst themselves.
Citations:
Jiang, et al. “Quorum Sensing: A Prospective Therapeutic Target for Bacterial Diseases.” BioMed Research International, Hindawi, 4 Apr. 2019, www.hindawi.com/journals/bmri/2019/2015978/.
Lee, Jasmine, and Lianhui Zhang. “The Hierarchy Quorum Sensing Network in Pseudomonas Aeruginosa.” Protein & Cell, Higher Education Press, Jan. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4286720/.
Li, Yung-Hua, and Xiaolin Tian. “Quorum Sensing and Bacterial Social Interactions in Biofilms.” Sensors (Basel, Switzerland), Molecular Diversity Preservation International (MDPI), 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3376616/.
Li, Zhi, and Satish K Nair. “Quorum Sensing: How Bacteria Can Coordinate Activity and Synchronize Their Response to External Signals?” Protein Science : a Publication of the Protein Society, Wiley Subscription Services, Inc., A Wiley Company, Oct. 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3526984/.
Miyashiro, Tim, and Edward G Ruby. “Shedding Light on Bioluminescence Regulation in Vibrio Fischeri.” Molecular Microbiology, U.S. National Library of Medicine, June 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3359415/.
“Pseudomonas Aeruginosa Infection.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 13 Nov. 2019, www.cdc.gov/hai/organisms/pseudomonas.html.
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What Did You Learn?
Questions:
1. What are quorum sensing mechanisms dependent upon?
Quorum sensing is dependent on cell density. When a population of bacteria reaches a certain threshold, known as a quorum, the concentration of signaling molecules reaches a threshold as well which triggers R-protein receptors to regulate transcription factors on prokaryotic operons.
2. Why do quorum sensing mechanisms pose additional medical implications?
Bacterial colonies that utilize quorum sensing, such as the species Pseudomonas aeruginosa, are capable of collectively responding to host immune system attacks by collectively communicating to increase the transcription and expression of genes that cause virulence factors, such as the release of toxins. Additionally, QS helps to coordinate the formation and detachment of biofilms and increased antibiotic resistance through plasmids and conjugation.
3. What is the most extensively studied and common mechanism of quorum sensing used in Gram-negative bacteria?
The AHL (acyl-homoserine lactones) class of autoinducers.