Chemotaxis


Chemotaxis is the movement of an organism or entity in response to a chemical stimulus. 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 by swimming toward the highest concentration of food molecules, or to flee from poisons. In multicellular organisms, chemotaxis is critical to early development and development as well as in normal function and health. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer metastasis, and the aberrant change of the overall property of these networks, which control chemotaxis, can lead to carcinogenesis. The aberrant chemotaxis of leukocytes and lymphocytes also contribute to inflammatory diseases such as atherosclerosis, asthma, and arthritis. Sub-cellular components, such as the polarity patch generated by mating yeast, may also display chemotactic behavior.
Positive chemotaxis occurs if the movement is toward a higher concentration of the chemical in question; negative chemotaxis if the movement is in the opposite direction. Chemically prompted kinesis can be called chemokinesis.

History of chemotaxis research

Although migration of cells was detected from the early days of the development of microscopy by Leeuwenhoek, a Caltech lecture regarding chemotaxis propounds that 'erudite description of chemotaxis was only first made by T. W. Engelmann and W. F. Pfeffer in bacteria, and H. S. Jennings in ciliates'. The Nobel Prize laureate I. Metchnikoff also contributed to the study of the field during 1882 to 1886, 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, and the most fundamental definitions underlying the phenomenon were 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 that became available to investigate the migratory responder cells and subcellular fractions responsible for chemotactic activity. The availability of this technology led to the discovery of C5a, a major chemotactic factor involved in acute inflammation. The pioneering works of J. Adler modernized Pfeffer's capillary assay and represented a significant turning point in understanding the whole process of intracellular signal transduction of bacteria.

Bacterial chemotaxis

Some bacteria, such as E. coli, have several flagella per cell. These can rotate in two ways:
  1. Counter-clockwise rotation aligns the flagella into a single rotating bundle, causing the bacterium to swim in a straight line; and
  2. 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, called run-and-tumble motion. As a result, the trajectory of a bacterium swimming in a uniform environment will form a biased random walk with relatively straight swims interrupted by random tumbles that reorient the bacterium. By repeatedly evaluating their course, and adjusting if they are moving in the wrong direction, bacteria can direct their random walk motion toward favorable locations.
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, it will keep swimming in a straight line for a longer time before tumbling; however, if it is moving in the wrong direction, it will tumble sooner. Peritrichous bacteria such as Escherichia coli use temporal sensing to decide whether their situation is improving or not, and in this way, find the location with the highest concentration of attractant, detecting even small differences in concentration. Salmonella typhimurium can also behave in this way, and also lophotrichous flagellated bacteria such as Pseudomonas putida, can actively influence the angular change between their swimming phases. As a result the swimming direction is biased in the direction of a better environmental condition for the bacteria. This could be advantageous for swimming in natural habitats such as tissue or soil, where the free path length is restricted and a bias in run length is ineffective.
For peritrichous flagellated bacteria, this biased random walk is a result of simply choosing between two methods of random movement; namely tumbling and straight swimming.
The helical nature of the individual flagellar filament is critical for this movement to occur. The protein structure that makes up the flagellar filament, flagellin, is conserved among all flagellated bacteria. Vertebrates seem to have taken advantage of this fact by possessing an immune receptor 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. Also lophotrichous flagellated bacteria such as Pseudomonas putida show different swimming modes.

Signal transduction

Chemical gradients are sensed through multiple transmembrane receptors, called methyl-accepting chemotaxis proteins, which vary in the molecules that they detect. Thousands of MACP receptors are known to be encoded across the bacterial kingdom. 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.

Flagellum regulation

The proteins CheW and CheA bind to the receptor. The absence of receptor activation results in 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; CheA is a histidine kinase and it does not actively transfer the phosphoryl group, rather, the response regulator CheB takes the phosphoryl group from CheA. This mechanism of signal transduction is called a two-component system, and it 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 will remain low, the cell will swim smoothly, and the level of methylation of the MCPs will increase. 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 increases and the cell begins to tumble. 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 repellents: fully methylated MCPs respond best to repellents, 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.
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.

Chemoattractants and chemorepellents

Chemoattractants and chemorepellents are inorganic or organic substances possessing chemotaxis-inducer effect in motile cells. These chemotactic ligands create chemical concentration gradients that organisms, prokaryotic and eukaryotic, move toward or away from, respectively.
Effects of chemoattractants are elicited via chemoreceptors such as methyl-accepting chemotaxis proteins. MCPs in E.coli include Tar, Tsr, Trg and Tap. Chemoattracttants to Trg include ribose and galactose with phenol as a chemorepellent. Tap and Tsr recognize dipeptides and serine as chemoattractants, respectively.
Chemoattractants or chemorepellents bind MCPs at its extracellular domain; an intracellular signaling domain relays the changes in concentration of these chemotactic ligands to downstream proteins like that of CheA which then relays this signal to flagellar motors via phosphorylated CheY. CheY-P can then control flagellar rotation influencing the direction of cell motility.
For E.coli, S. meliloti, and R. spheroides, the binding of chemoattractants to MCPs inhibit CheA and therefore CheY-P activity, resulting in smooth runs, but for B. substilis, CheA activity increases. Methylation events in E.coli cause MCPs to have lower affinity to chemoattractants which causes increased activity of CheA and CheY-P resulting in tumbles. In this way cells are able to adapt to the immediate chemoattractant concentration and detect further changes to modulate cell motility.
Chemoattractants in eukaryotes are well characterized for immune cells. Formyl peptides, such as fMLF, attract leukocytes such as neutrophils and macrophages, causing movement toward infection sites. Non-acylated methioninyl peptides do not act as chemoattractants to neutrophils and macrophages. Leukocytes also move toward chemoattractants C5a, a complement component, and pathogen-specific ligands on bacteria.
Mechanisms concerning chemorepellents are less known than chemoattractants. Although chemorepellents work to confer an avoidance response in organisms, Tetrahymena thermophila adapt to a chemorepellent, Netrin-1 peptide, within 10 minutes of exposure; however, exposure to chemorepellents such as GTP, PACAP-38, and nociceptin show no such adaptations. GTP and ATP are chemorepellents in micro-molar concentrations to both Tetrahymena and Paramecium. These organisms avoid these molecules by producing avoiding reactions to re-orient themselves away from the gradient.