User:Cathalgarvey/SpecialBookPages/BacterialChemotaxis

Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food (for example, glucose) by swimming towards the highest concentration of food molecules, or to flee from poisons (for example, phenol). In multicellular organisms, chemotaxis is critical to early development (e.g. movement of sperm towards the egg during fertilization) and subsequent phases of development (e.g. migration of neurons or lymphocytes) as well as in normal function. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer metastasis.

Positive chemotaxis occurs if the movement is towards a higher concentration of the chemical in question. Conversely, negative chemotaxis occurs if the movement is in the opposite direction.

History of chemotaxis research

Neutrophils are the body's first line of defense against bacterial infections. After leaving nearby blood vessels, these cells recognize chemicals produced by bacteria in a cut or scratch and migrate "toward the smell". The above neutrophils were placed in a gradient of fMLP (N-formyl-methionine-leucine-phenylalanine), a peptide chain produced by some bacteria. Although migration of cells was detected from the early days of the development of microscopy (Leeuwenhoek), erudite description of chemotaxis was first made by T W. Engelmann (1881) and W.F. Pfeffer (1884) in bacteria and H.S. Jennings (1906) in ciliates. The Nobel Prize laureate I. Metchnikoff also contributed to the study of the field with investigations of the process as an initial step of phagocytosis. The significance of chemotaxis in biology and clinical pathology was widely accepted in the 1930s. The most fundamental definitions belonging to the phenomenon were also drafted by this time. The most important aspects in quality control of chemotaxis assays were described by H. Harris in the 1950s. In the 1960s and 1970s, the revolution of modern cell biology and biochemistry provided a series of novel techniques which became available to investigate the migratory responder cells and subcellular fractions responsible for chemotactic activity. The pioneering works of J. Adler represented a significant turning point in understanding the whole process of intracellular signal transduction of bacteria.^[1]

On November 3, 2006, Dr. Dennis Bray of University of Cambridge was awarded the Microsoft Award for his work on chemotaxis on E. coli.^[2]^[3]

Chemoattractants and chemorepellents

Chemoattractants and chemorepellents are inorganic or organic substances possessing chemotaxis-inducer effect in motile cells. Effects of chemoattractants are elicited via described or hypothetic chemotaxis receptors, the chemoattractant moiety of a ligand is target cell specific and concentration dependent. Most frequently investigated chemoattractants are formyl peptides and chemokines. Responses to chemorepellents result in axial swimming and they are considered a basic motile phenomena in bacteria. The most frequently investigated chemorepellents are inorganic salts, amino acids and some chemokines.

Bacterial chemotaxis

Some bacteria, such as E. coli, have several flagella per cell (4–10 typically). These can rotate in two ways :

Counter-clockwise rotation aligns the flagella into a single rotating bundle, causing the bacterium to swim in a straight line.
Clockwise rotation breaks the flagella bundle apart such that each flagellum points in a different direction, causing the bacterium to tumble in place.

The directions of rotation are given for an observer outside the cell looking down the flagella toward the cell.

Behavior

The overall movement of a bacterium is the result of alternating tumble and swim phases. If one watches a bacterium swimming in a uniform environment, its movement will look like a random walk with relatively straight swims interrupted by random tumbles that reorient the bacterium. Bacteria such as E. coli are unable to choose the direction in which they swim, and are unable to swim in a straight line for more than a few seconds due to rotational diffusion. In other words, bacteria "forget" the direction in which they are going. By repeatedly evaluating their course, and adjusting if they are moving in the wrong direction, bacteria can direct their motion to find favorable locations with high concentrations of attractants (usually food) and avoid repellents (usually poisons).

In the presence of a chemical gradient bacteria will chemotax, or direct their overall motion based on the gradient. If the bacterium senses that it is moving in the correct direction (toward attractant/away from repellent), it will keep swimming in a straight line for a longer time before tumbling. If it is moving in the wrong direction, it will tumble sooner and try a new direction at random. In other words, bacteria like E. coli use temporal sensing to decide whether life is getting better or worse. In this way, it finds the location with the highest concentration of attractant (usually the source) quite well. Even under very high concentrations, it can still distinguish very small differences in concentration. Fleeing from a repellent works with the same efficiency.

This purposeful random walk is a result of simply choosing between two methods of random movement; namely tumbling and straight swimming. In fact, chemotactic responses such as forgetting direction and choosing movements resemble the decision-making abilities of higher life-forms with brains that process sensory data.

The helical nature of the individual flagellar filament is critical for this movement to occur. As such, the protein that makes up the flagellar filament, flagellin, is quite similar among all flagellated bacteria. Vertebrates seem to have taken advantage of this fact by possessing an immune receptor (TLR5) designed to recognize this conserved protein.

As in many instances in biology, there are bacteria that do not follow this rule. Many bacteria, such as Vibrio, are monoflagellated and have a single flagellum at one pole of the cell. Their method of chemotaxis is different. Others possess a single flagellum that is kept inside the cell wall. These bacteria move by spinning the whole cell, which is shaped like a corkscrew.^[4]

Signal transduction

Chemical gradients are sensed through multiple transmembrane receptors, called methyl-accepting chemotaxis proteins (MCPs), which vary in the molecules that they detect. These receptors may bind attractants or repellents directly or indirectly through interaction with proteins of periplasmatic space. The signals from these receptors are transmitted across the plasma membrane into the cytosol, where Che proteins are activated. The Che proteins alter the tumbling frequency, and alter the receptors.

Domain structure of chemotaxis receptor for Asp

Flagellum regulation

The proteins CheW and CheA bind to the receptor. The activation of the receptor by an external stimulus causes autophosphorylation in the histidine kinase, CheA, at a single highly conserved histidine residue. CheA in turn transfers phosphoryl groups to conserved aspartate residues in the response regulators CheB and CheY [ note: CheA is a histidine kinase and it does not actively transfer the phosphoryl group. The response regulator CheB takes the phosphoryl group from CheA]. This mechanism of signal transduction is called a two-component system and is a common form of signal transduction in bacteria. CheY induces tumbling by interacting with the flagellar switch protein FliM, inducing a change from counter-clockwise to clockwise rotation of the flagellum. Change in the rotation state of a single flagellum can disrupt the entire flagella bundle and cause a tumble.

Receptor regulation

CheB, when activated by CheA, acts as a methylesterase, removing methyl groups from glutamate residues on the cytosolic side of the receptor. It works antagonistically with CheR, a methyltransferase, which adds methyl residues to the same glutamate residues. If the level of an attractant remains high, the level of phosphorylation of CheA (and therefore CheY and CheB) will remain low, the cell will swim smoothly, and the level of methylation of the MCPs will increase (because CheB-P is not present to demethylate). However, the MCPs no longer respond to the attractant when they are fully methylated. Therefore, even though the level of attractant might remain high, the level of CheA-P (and CheB-P) increases and the cell begins to tumble. However, now the MCPs can be demethylated by CheB-P, and when this happens, the receptors can once again respond to attractants. The situation is the opposite with regard to repellants (fully methylated MCPs respond best to repellants, while least methylated MCPs respond worst to repellents). This regulation allows the bacterium to 'remember' chemical concentrations from the recent past, a few seconds, and compare them to those it is currently experiencing, thus 'know' whether it is traveling up or down a gradient. Although the methylation system accounts for the wide range of sensitivity ^[5] that bacteria have to chemical gradients, other mechanisms are involved in increasing the absolute value of the sensitivity on a given background. Well established examples are the ultra-sensitive response of the motor to the CheY-P signal, and the clustering of chemoreceptors.^[6]^[7]

References

^ Julius Adler and Wung-Wai Tso (1974). "Decision-Making in Bacteria: Chemotactic Response of Escherichia Coli to Conflicting Stimuli". Science. 184 (4143): 1292–4. doi:10.1126/science.184.4143.1292. PMID 4598187.
^ U.K. Professor Captures Inaugural European Science Award, By Rob Knies, News - Microsoft Research, retrieved November 6, 2006^{[dead link]}Archive index at the Wayback Machine
^ Computer bug study wins top prize, 3 November 2006, BBC NEWS, retrieved November 6, 2006
^ Howard C. Berg (2003). "E. coli in motion". Springer-Verlag, NY. ISBN 0-387-00888-8. New York: Springer. ISBN 0387008888. {{cite journal}}: templatestyles stripmarker in |volume= at position 1 (help)
^ Bernardo A. Mello and Yuhai Tu (2007). "Effects of Adaptation in Maintaining High Sensitivity over a Wide Range of Backgrounds for Escherichia coli Chemotaxis". Biophysical Journal. 92 (7): 2329–2337. doi:10.1529/biophysj.106.097808. PMC 1864821. PMID 17208965.
^ Philippe Cluzel, Michael Surette and Stanislas Leibler (2000). "An Ultrasensitive Bacterial Motor Revealed by Monitoring Signaling Proteins in Single Cells". Science. 287 (5458): 1652–1655. doi:10.1126/science.287.5458.1652. PMID 10698740.
^ Victor Sourjik; Tso, WW (2004). "Receptor clustering and signal processing in E. coli chemotaxis". TRENDS in Microbiology. 12 (12): 569–576. doi:10.1016/j.tim.2004.10.003. PMID 15539117.