Bacteria as Social Organisms

By Michael Wade 

If you wanted to move a piano from your old apartment on the second floor to your new house, you wouldn’t try to move it by yourself because it’s too heavy. The logical thing to do would be to call a bunch of your friends and have them help, distributing the weight of the piano among many people instead of just one. Well…bacteria can do a similar thing of working together for a common good called quorum sensing. A few decades ago, everyone thought of bacteria as individuals doing their own thing. However, that is not the case, for if it were, bacteria would most likely not be as successful of an organism as they are.

Quorum sensing works by bacteria secreting a soluble small molecule called an “autoinducer” (AI) or a “pheromone”.  The AI then diffuses through the environment and can be taken up by the same bacteria or another bacteria in the same area. At low numbers of bacteria, there isn’t a lot of AI in the environment, but after a few rounds of cell division, the numbers of bacteria increase exponentially and so does the concentration of AIs. At this point, the AI’s are binding to receptors or diffusing into the cell at a high concentration. The bacteria “senses” that there are a lot of other bacteria around, and once the concentration reaches a certain point, gene expression changes for all the bacteria in that localized area, allowing the bacteria to work together for a common good or goal.

AIs are not all the same, nor does each bacteria only produce one AI. The structure of AIs and how many AIs an organism produces or responds to is different for each organism. Gram-negative bacteria tend to synthesize some variation of an acyl-homoserine lactone (AHL) molecule, while Gram-positive bacteria tend to use small amino acid sequences. Due to the differences in molecules, the mechanisms are slightly different. Gram-negative AIs can diffuse in and out of a cell and can interact with intracellular proteins or with surface sensor protein, whereas Gram-positive AIs have to be actively transported out of the cell and only interact with surface sensor proteins.

What kind of goal could bacteria be trying to achieve by working together? Well, there are many. When bacteria reach the critical density and start changing gene expression, they tend to shift toward making “public goods” instead of “private goods”. What that means is bacteria will make extracellular enzymes that break down the macromolecules in their environment into smaller molecules that can then be used for energy instead of keeping their enzymes tethered or inside the cell, or make and secrete molecules used for biofilms. These secreted enzymes are “public goods” because all the bacteria in the area benefit from products of the enzymes. The benefits of quorum sensing can be seen in various situations and environments, from Vibrio fischeri in the light organ of it’s squid host, to Vibrio cholerae and many other species in biofilms, to Pseudomonas aeruginosa in an opportunistic infection in a cystic fibrosis patient. However, making the “public goods” comes at a high cost in that it takes a lot of energy, which leads to the evolution of social cheaters. Social cheaters are bacteria that benefit from “public goods” of cooperators but don’t respond to quorum sensing signals. Although they tend to arise only after many generations of replication, they outcompete cooperators once they have been established as a subpopulation, but then rapidly collapse, a tragedy of the commons.

There are many examples of bacteria that are known to communicate, but I’ll only mention a few. Vibrio fischeri, and Vibrio harveyi are bioluminescent marine bacteria that are used as models for quorum sensing. V. fischeri is a symbiont that colonizes the light organ of the Hawaiian bobtail squid and provide light during the night as counter-illumination to prevent predation on the squid. Once V. fischeri enters the light organ, it begins to divide, and in a short amount of time, the concentration reaches a threshold amount, as signaled by AI concentration, that V. fischeri changes global gene expression through a phosphorylation cascade that results in a stable master regulator (LitR/HapR) that activates many target genes and operons, one of which is responsible for luminescence. The quorum sensing mechanism in V. harveri is very similar to that of V. fischeri with similar gene products. However, since V. harveyi is an opportunistic fish pathogen, the AIs also target genes for toxins and virulence factors.

Because humans are selfish, research in quorum sensing has recently been in bacteria that cause disease in humans. During infections, survival and colonization in hostile host environments is important for bacteria. The ability to remain undercover from the host defenses until the bacteria population is dense enough to overwhelm the host immune defenses is a common theme, and is modulated through quorum sensing. Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute and chronic infections in immunocompromised individuals, and is a major concern in cystic fibrosis patients. P.aeruginosa is a Gram-negative bacteria, so it uses AHL molecules to asses its population density. Once it reaches a critical density, P. aeruginosa launches a full blown attack against the host, secreting exotoxins, proteases, cyanide, and many other exoproducts-some of which are dependent upon the environmental factors. However, the AIs also have a secondary role to assessing population density-they also can inhibit host defenses such as macrophage proliferation or switch the T helper response from the antibacterial Th1 response to the Th2 response. Another pathogen known to quorum sense is Yersiniae pestis, the causative agent of plague.

The ability to assess the population is not limited to assessing individual species numbers-bacteria can communicate across species. Cross-species communication may be important for survival in various niches such as biofilms. Although some AIs are very specific for a particular species, others are more generalized and can function across Genus’s. In the figure below, the V. harveyi mutant can’t make the autoinducer HAI. However, the E.coli next to the V. harveryi does produce a HAI-like autoinducer, allowing only the V. harveyi cells next to the E. coli cells to respond to that signal, resulting in luminescence (a quorum sensing product)

So, now that we know bacteria communicate to work together, what can we do to prevent this communication in pathogenic bacterial infections? Well, chemists have teamed up with microbiologists to synthesize quorum sensing analog molecules for both Gram positive and Gram-negative bacteria. The goal of the analogs is not to kill the bacteria, but to down-regulate virulence factors, which as we learned earlier, are products of quorum sensing. However, although many bacteria posses the AI system, this type of approach may be very limited becuase P. aeurginosa is the only major human pathogen known to use AHLs for controlling virulence factors. In related research, chemists have developed a molecule that blocks the quorum sensing system in Staphylococcus aureus that is responsible for virulence factors. Although it’s only been tested in a mouse skin model, this novel treatment could be of importance due to the growing antimicrobial resistance in many species, especially S. aureus (methicillin, vancomycin).

Quorum sensing is a young subject that is attracting a lot attention from scientists, with more and more labs dedicated to understanding this awesome phenomenon of bacteria as complex, social organisms.

References:

Bassler, B.L., Greenberg, E.P., and A.M. Stevens. 1997. Cross-Species Induction of Luminesence in the Quorum-Sensing Bacterium Vibrio harveyi. Journal of Bacteriology 179:4043-4045.

Dandekar, A.A., Chugani, S., and E.P. Greenberg. 2013. Bacterial Quorum sensing and Metabolic Incentives to Cooperate. Science 338:264-266.

Nyholm, S.V., and M.J. McFall-Ngai. 2004. The Winnowing-Establishing the Squid-Vibrio Symbiosis. Nature 2:632-642.

Sandoz, K.M., Mitzimberg, S.M., and M. Schuster. 2007. Social cheating in Pseudomonas aeruginosa quorum sensing. Proceedings of the National Academy of Science 104:15876-15881.

Williams, P., Camara, M., Hardman, A., Swift, S., Milton, D., Hope, V.J., Winzer, K., Middleton, B., Pritchard, D.I., and B.W. Bycroft. 2000. Quorum sensing and the Population-Dependent Control of Virulence. The Royal Society 355:667-680.