Chemotaxis
Encyclopedia
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 poison
s (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 neuron
s or lymphocyte
s) 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.
(1881) and W.F. Pfeffer
(1884) in bacteria and H.S. Jennings
(1906) in ciliate
s. 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 assay
s 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.
On November 3, 2006, Dr. Dennis Bray
of University of Cambridge
was awarded the Microsoft Award
for his work on chemotaxis on E. coli
.
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 peptide
s and chemokine
s. 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 chemokine
s.
, such as E. coli, have several flagella
per cell (4–10 typically). These can rotate in two ways :
The directions of rotation are given for an observer outside the cell looking down the flagella toward the cell.
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 (TLR
5) 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.
, where Che proteins are activated. The Che proteins alter the tumbling frequency, and alter the receptors.
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.
, removing methyl groups from glutamate residues on the cytosol
ic 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 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. Although the methylation system accounts for the wide range of sensitivity 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.
Levels of receptors, intracellular signalling pathways and the effector mechanisms all represent diverse, eukaryotic type components. In eukaryotic unicellular cells, ameboid movement and cilium or the eukaryotic flagellum are the main effectors (e.g. Amoeba
or Tetrahymena
). Some eukaryotic cells of higher vertebrate origin, such as immune cells
also move to where they need to be. Besides immune competent cells (granulocyte
, monocyte
, lymphocyte
) a large group of cells - considered previously to be fixed into tissues - are also motile in special physiological (e.g. mast cell
, fibroblast
, endothelial cells)or pathological conditions (e.g. metastases). Chemotaxis has high significance in the early phases of embryogenesis
as development of germ layers is guided by gradients of signal molecules.
filaments. The growing distal end of actin filaments develops connections with the internal surface of the plasma membrane via different sets of peptides and results in the formation of pseudopods.
Cilia
of eukaryotic cells can also produce chemotaxis; in this case it is mainly a Ca2+ dependent induction of the microtubular
system of the basal body
and the beat of the 9+2 microtubules within cilia. The orchestrated beating of hundreds of cilia is synchronized by a submembranous system built between basal bodies.
The details of the signaling pathways are still not totally clear.
coupled receptors. This class of receptors is huge, representing a significant portion of the genome
. Some members of this gene superfamily are used in eyesight (rhodopsins) as well as in olfaction (smelling).
The main classes of professional chemotaxis receptors are triggered by formyl peptides - formyl peptide receptor
s (FPR), chemokines - chemokine receptor
s (CCR or CXCR) and leukotrienes - leukotriene receptors (BLT); however, induction of a wide set of membrane receptors (e.g. amino acids, insulin
, vasoactive peptides) also elicit migration of the cell.
we can determine whether a still uncharacterized molecule acts via the long- or the short-term receptor pathway.
The term chemotactic selection is also used to designate a technique which separates eukaryotic or prokaryotic cells according to their chemotactic responsiveness to selector ligands.
Investigations of the three-dimensional structures of chemokines proved that a characteristic composition of beta-sheets and an alpha helix provides expression of sequences required for interaction with the chemokine receptors. Formation of dimers and their increased biological acitvity was demonstrated by crystallography of several chemokines e.g. IL-8.
Altered chemotactic activity of extracellular (e.g. Escherichia coli
) or intracellular (e.g. Listeria monocytogenes) pathogens itself represents a significant clinical target. Modification of endogenous chemotactic ability of these microorganisms by pharmaceutical agents can decrease or inhibit the ratio of infections or spreading of infectious diseases.
Apart from infections, there are some other diseases where impaired chemotaxis is the primary etiological factor, as in Chediak-Higashi syndrome
where giant intracellular vesicles inhibit normal migration of cells.
Although interactions of the factors listed above make the behavior of the solutions of mathematical models of chemotaxis rather complex, it is possible to describe the basic phenomenon of chemotaxis-driven motion in a straightforward way.
Indeed, let us denote with
the spatially non-uniform concentration of the chemo-attractant and with 
its gradient. Then the chemotactic cellular flow (also called current) 
that is generated by the chemotaxis is linked to the above gradient by the law: 
, where 
is the spatial density of the cells and 
is the so-called ’Chemotactic coefficient’. However, note that in many cases 
is not constant: it is, instead, a decreasing function of the concentration of the chemo-attractant 
: 
.
s dealing with itself the phenomenon chemotaxis. Nevertheless, other publications written in genetics
, biochemistry
, cell-physiology, pathology
and clinical sciences could also incorporate data about migration or especially the chemotaxis of cells. A curiosity of migration research is that among several works investigating taxes (e.g.thermotaxis
, geotaxis, phototaxis
) chemotaxis research shows a significantly high ratio, which point to the underlined importance of chemotaxis research both in biology
and medicine
.
The basic requirements of the measurement are as follows:
Despite the fact that an ideal chemotaxis assay
is still not available, there are several protocols and pieces of equipment which offer good correspondence with the conditions described above. The most commonly used are summarised in the table below:
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, 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
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
) by swimming towards the highest concentration of food molecules, or to flee from poison
Poison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
s (for example, phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
). In multicellular organisms, chemotaxis is critical to early development (e.g. movement of sperm
Sperm
The term sperm is derived from the Greek word sperma and refers to the male reproductive cells. In the types of sexual reproduction known as anisogamy and oogamy, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell...
towards the egg during fertilization) and subsequent phases of development (e.g. migration of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s or lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s) as well as in normal function. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.
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. EngelmannTheodor Wilhelm Engelmann
Theodor Wilhelm Engelmann was a German botanist, physiologist, microbiologist, university professor, and musician whose 1882 experiment measured the effects of different colors of light on photosynthetic activity and showed that the conversion of light energy to chemical energy took place in the...
(1881) and W.F. Pfeffer
Wilhelm Pfeffer
Wilhelm Friedrich Philipp Pfeffer was a German botanist and plant physiologist who was born in Grebenstein.- Academic career :...
(1884) in bacteria and H.S. Jennings
Herbert Spencer Jennings
-External links:**]]...
(1906) in ciliate
Ciliate
The ciliates are a group of protozoans characterized by the presence of hair-like organelles called cilia, which are identical in structure to flagella but typically shorter and present in much larger numbers with a different undulating pattern than flagella...
s. 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 assay
Chemotaxis assay
Chemotaxis assays are experimental tools for evaluation of chemotactic ability of prokaryotic or eukaryotic cells.A wide variety of techniques are known and applied for such reason...
s 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
Julius Adler (biochemist)
Julius Adler Ph.D. is an American biochemist. He has been an Emeritus Professor of biochemistry and genetics at the University of Wisconsin–Madison since 1997.-Early life:...
represented a significant turning point in understanding the whole process of intracellular signal transduction of bacteria.
On November 3, 2006, Dr. Dennis Bray
Dennis Bray
Dennis Bray is an active emeritus professor at University of Cambridge. His group is also part of the Oxford Centre for Integrative Systems Biology...
of University of Cambridge
University of Cambridge
The University of Cambridge is a public research university located in Cambridge, United Kingdom. It is the second-oldest university in both the United Kingdom and the English-speaking world , and the seventh-oldest globally...
was awarded the Microsoft Award
Microsoft Award
The Royal Society and Académies des sciences Microsoft Award is an annual award given by the Royal Society and the Académie des sciences to scientists working in Europe who have made a major contribution to the advancement of science through the use of computational methods...
for his work on chemotaxis on E. coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
.
Chemoattractants and chemorepellents
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
substances possessing chemotaxis-inducer effect in motile cells. Effects of chemoattractants are elicited via described or hypothetic chemotaxis receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, the chemoattractant moiety of a ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
is target cell specific and concentration dependent. Most frequently investigated chemoattractants are formyl peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
s and chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s. Responses to chemorepellents result in axial swimming and they are considered a basic motile
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
phenomena in bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. The most frequently investigated chemorepellents are inorganic salts, amino acids and some chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s.
Bacterial chemotaxis
Some bacteriaBacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, such as E. coli, have several flagella
Flagellum
A flagellum is a tail-like projection that protrudes from the cell body of certain prokaryotic and eukaryotic cells, and plays the dual role of locomotion and sense organ, being sensitive to chemicals and temperatures outside the cell. There are some notable differences between prokaryotic and...
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 walkRandom walk
A random walk, sometimes denoted RW, is a mathematical formalisation of a trajectory that consists of taking successive random steps. For example, the path traced by a molecule as it travels in a liquid or a gas, the search path of a foraging animal, the price of a fluctuating stock and the...
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
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
. 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
Gradient
In vector calculus, the gradient of a scalar field is a vector field that points in the direction of the greatest rate of increase of the scalar field, and whose magnitude is the greatest rate of change....
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
Biased random walk (biochemistry)
In cell biology, a biased random walk enables bacteria to search for food and flee from harm. Bacteria propel themselves with the aid of flagella in a process called chemotaxis, and a typical bacteria trajectory has many characteristics of a random walk. They move forward for a certain distance,...
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
Flagellin
Flagellin is a protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum. It has a mass of about 30,000 to 60,000 daltons...
, is quite similar among all flagellated bacteria. Vertebrates seem to have taken advantage of this fact by possessing an immune receptor (TLR
TLR
The three letter abbreviation TLR can mean* Toll-like receptors, proteins constituting an important part of the immune system* Tonic labyrinthine reflex, a primitive reflex found in newborn humans* Twin-lens reflex camera, a photo camera with two lenses...
5) 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.
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 cytosolCytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, 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 activation of the receptor by an external stimulus causes autophosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
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
Protein-glutamate methylesterase
In enzymology, a protein-glutamate methylesterase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are protein L-glutamate O5-methyl ester and H2O, whereas its two products are protein L-glutamate and methanol....
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 methylesteraseDemethylase
Demethylases are enzymes that remove methyl groups from proteins and other substances. They are used in a variety of processes, such as in chemotaxis signal transduction.-Hydrolytic demethylation:A good example of a demethylase is the activated Demethylases are enzymes that remove methyl (CH3-)...
, removing methyl groups from glutamate residues on the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
ic side of the receptor. It works antagonistically with CheR, a methyltransferase
Transferase
In biochemistry, a transferase is an enzyme that catalyzes the transfer of a functional group from one molecule to another . For example, an enzyme that catalyzed this reaction would be a transferase:In this example, A would be the donor, and B would be the acceptor...
, 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 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. Although the methylation system accounts for the wide range of sensitivity 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.
Eukaryotic chemotaxis
The mechanism by which eukaryotic cells chemotax is quite different from that in bacteria; however, sensing of chemical gradients is still a crucial step in the process. Due to their size, prokaryotes cannot detect effective concentration gradients, therefore these cells scan and evaluate their environment by a constant swimming (consecutive steps of straight swims and tumbles). In contrast to prokaryotes, the size of eukaryotic cells allows for the possibility of detecting gradients, which results in a dynamic and polarized distribution of receptors. Induction of these receptors by chemoattractants or chemorepellents results in migration towards or away from the chemotactic substance.Amoeba
Amoeba is a genus of Protozoa.History=The amoeba was first discovered by August Johann Rösel von Rosenhof in 1757. Early naturalists referred to Amoeba as the Proteus animalcule after the Greek god Proteus, who could change his shape...
or Tetrahymena
Tetrahymena
Tetrahymena are free-living ciliate protozoa that can also switch from commensalistic to pathogenic modes of survival. They are common in fresh-water. Tetrahymena species used as model organisms in biomedical research are T. thermophila and T. pyriformis.- T...
). Some eukaryotic cells of higher vertebrate origin, such as immune cells
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
also move to where they need to be. Besides immune competent cells (granulocyte
Granulocyte
Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...
, monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
, lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
) a large group of cells - considered previously to be fixed into tissues - are also motile in special physiological (e.g. mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
, fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
, endothelial cells)or pathological conditions (e.g. metastases). Chemotaxis has high significance in the early phases of embryogenesis
Embryogenesis
Embryogenesis is the process by which the embryo is formed and develops, until it develops into a fetus.Embryogenesis starts with the fertilization of the ovum by sperm. The fertilized ovum is referred to as a zygote...
as development of germ layers is guided by gradients of signal molecules.
Motility
Unlike motility in bacterial chemotaxis, the mechanism by which eukaryotic cells physically move is unclear. There appear to be mechanisms by which an external chemotactic gradient is sensed and turned into an intracellular PIP3 gradient, which results in a gradient and the activation of a signaling pathway, culminating in the polymerisation of actinActin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
filaments. The growing distal end of actin filaments develops connections with the internal surface of the plasma membrane via different sets of peptides and results in the formation of pseudopods.
Cilia
Cilium
A cilium is an organelle found in eukaryotic cells. Cilia are slender protuberances that project from the much larger cell body....
of eukaryotic cells can also produce chemotaxis; in this case it is mainly a Ca2+ dependent induction of the microtubular
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
system of the basal body
Basal body
A basal body is an organelle formed from a centriole, and a short cylindrical array of microtubules. It is found at the base of a eukaryotic undulipodium and serves as a nucleation site for the growth of the axoneme microtubules...
and the beat of the 9+2 microtubules within cilia. The orchestrated beating of hundreds of cilia is synchronized by a submembranous system built between basal bodies.
The details of the signaling pathways are still not totally clear.
Chemotaxis related migratory responses
Although chemotaxis is the most frequently studied form of migration there are several other forms of locomotion in the cellular level.- ChemokinesisChemokinesisMotile response of unicellular prokaryotic or eukaryotic organisms to chemicals that cause the cell to make some kind of change in their migratory/swimming behaviour. Changes involve an increase or decrease of speed, alterations of amplitude or frequency of motile character, or direction of migration...
is also induced by molecules of the liquid phase of the surrounding environment; however, the response elicited is a not vectorial, random taxis. Neither amplitude nor frequency of motion has characteristic, directional components as this behaviour provides more scanning of the environment than migration between two distinct points. - In haptotaxisHaptotaxisHaptotaxis is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or substrate-bound chemoattractants...
the gradientGradientIn vector calculus, the gradient of a scalar field is a vector field that points in the direction of the greatest rate of increase of the scalar field, and whose magnitude is the greatest rate of change....
of the chemoattractant is expressed or bound on a surface, in contrast to the classical model of chemotaxis, in which the gradient develops in a soluble fluid. The most common biologically active haptotactic surface is the extracellular matrixExtracellular matrixIn biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
(ECM); the presence of bound ligands is responsible for induction of transendothelial migration and angiogenesisAngiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. - Necrotaxis embodies a special type of chemotaxis when the chemoattractant molecules are released from necroticNecrosisNecrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
or apoptoticApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
cells. Depending on the chemical character of released substances, necrotaxis can accumulate or repel cells, which underlines the pathophysiological significance of this phenomenon.
Receptors
For the most part, eukaryotic cells sense the presence of chemotactic stimuli through the use of 7-transmembrane (or serpentine) heterotrimeric G-proteinG protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
coupled receptors. This class of receptors is huge, representing a significant portion of the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. Some members of this gene superfamily are used in eyesight (rhodopsins) as well as in olfaction (smelling).
The main classes of professional chemotaxis receptors are triggered by formyl peptides - formyl peptide receptor
Formyl peptide receptor
The formyl peptide receptors are a members of a class of G protein-coupled receptors involved in chemotaxis. These receptors where originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells...
s (FPR), chemokines - chemokine receptor
Chemokine receptor
Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. There have been 19 distinct chemokine receptors described in mammals...
s (CCR or CXCR) and leukotrienes - leukotriene receptors (BLT); however, induction of a wide set of membrane receptors (e.g. amino acids, insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, vasoactive peptides) also elicit migration of the cell.
Chemotactic selection
While some chemotaxis receptors are expressed in the surface membrane with long-term characteristics as they are determined genetically, others have short-term dynamics as they are assembled ad hoc in the presence of the ligand. The diverse features of the chemotaxis receptors and ligands allows for the possibility of selecting chemotactic responder cells with a simple chemotaxis assay. By chemotactic selectionChemotactic selection
Chemotaxis receptors are expressed in the surface membrane with diverse dynamics, some of them have long-term characteristics as they are determined genetically, others have short-term moiety as their assembly is induced ad hoc in the presence of the ligand...
we can determine whether a still uncharacterized molecule acts via the long- or the short-term receptor pathway.
The term chemotactic selection is also used to designate a technique which separates eukaryotic or prokaryotic cells according to their chemotactic responsiveness to selector ligands.
Chemotactic ligands
The number of molecules capable of eliciting chemotactic responses is relatively high, and we can distinguish primary and secondary chemotactic molecules. The main groups of the primary ligands are as follows:- Formyl peptides are di-, tri-, tetrapeptides of bacterial origin (see formyl group on the N terminus of the peptide). They are released from bacteria in vivo or after decomposition of the cell. A typical member of this group is the N-formylmethionyl-leucyl-phenylalanine (fMLF or fMLP in references). The bacterial origin fMLF as a key component of inflammation has characteristic chemoattractant effects in neutrophil granulocytes and monocytes.
- Complement 3a (C3aC3 (complement)Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.-Function:...
) and complement 5a (C5aC5aC5a is a protein fragment released from complement component C5. In humans, the polypeptide contains 74 amino acids. NMR spectroscopy proved that the molecule is composed of four helices and loops connecting the helices. On the N terminus a short 1.5 turn helix is also present. The longest helix...
) are intermediate products of complement cascade. Their synthesis is joined to the three alternative pathways (classical, lectin dependent and alternative) of complement activation by a convertase enzyme. The main target cells of these derivaties are neutrophil granulocytes and monocytes as well. - Chemokines belong to a special class of cytokines. Their groups (C, CC, CXC, CX3C chemokines) represent not only structurally related molecules with a special arrangement of disulfide bridges, but their target cell specificity is also diverse: CC chemokines act on monocytes (e.g. RANTESRANTESChemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. It is also known as RANTES .- Function :...
), CXC chemokines are neutrophil granulocyte specific (e.g. IL-8IL-8IL-8 can refer to:* Interleukin 8, a chemokine of the immune system* Illinois' 8th congressional district* Illinois Route 8...
).
- Leukotrienes belong to the group eicosanoids. They are significant lipid mediators of the arachidonic acid cascade converted by 5-lipoxigenase. Their predominant member is leukotriene B4 (LTB4) which elicits adhesion, chemotaxis and aggregation of leukocytes. The characteristic chemoattractant effect of LTB4 is induced via G-protein linked seven-transmembrane spanning leukotriene receptors which are highly expressed in inflammationInflammationInflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and allergyAllergyAn Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
.
Chemotactic range fitting (CRF)
Chemotactic responses elicited by the ligand-receptor interactions are distinguished generally upon the optimal effective concentration(s) of the ligand. Nevertheless, correlation of the amplitude elicited and ratio of the responder cells compared to the total number are also characteristic features of the chemotactic signaling. Investigations of ligand families (e.g. amino acids or oligo peptides) proved that there is a fitting of ranges (amplitudes; number of responder cells) and chemotactic activities: chemoattractant moiety is accompanied by wide ranges, while chemorepellent character by narrow ranges.Clinical significance
A changed migratory potential of cells has relatively high importance in the development of several clinical symptoms and syndromes.Altered chemotactic activity of extracellular (e.g. Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
) or intracellular (e.g. Listeria monocytogenes) pathogens itself represents a significant clinical target. Modification of endogenous chemotactic ability of these microorganisms by pharmaceutical agents can decrease or inhibit the ratio of infections or spreading of infectious diseases.
Apart from infections, there are some other diseases where impaired chemotaxis is the primary etiological factor, as in Chediak-Higashi syndrome
Chédiak-Higashi syndrome
Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy...
where giant intracellular vesicles inhibit normal migration of cells.
| Type of disease | Chtx. increased | Chtx. decreased |
|---|---|---|
| Infections | inflammation Inflammation Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process... s |
AIDS AIDS Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus... , Brucellosis Brucellosis Brucellosis, also called Bang's disease, Crimean fever, Gibraltar fever, Malta fever, Maltese fever, Mediterranean fever, rock fever, or undulant fever, is a highly contagious zoonosis caused by ingestion of unsterilized milk or meat from infected animals or close contact with their secretions... |
| Chtx. results the disease | - | Chediak-Higashi syndrome Chédiak-Higashi syndrome Chédiak–Higashi syndrome is a rare autosomal recessive disorder that arises from a microtubule polymerization defect which leads to a decrease in phagocytosis. The decrease in phagocytosis results in recurrent pyogenic infections, partial albinism and peripheral neuropathy... , Kartagener syndrome |
| Chtx. is affected | atherosclerosis Atherosclerosis Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol... , arthritis Arthritis Arthritis is a form of joint disorder that involves inflammation of one or more joints.... , periodontitis, psoriasis Psoriasis Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of... , reperfusion injury Reperfusion injury Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and... , metastatic tumors |
multiple sclerosis Multiple sclerosis Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms... , Hodgkin disease, male infertility Male infertility Male infertility refers to the inability of a male to achieve a pregnancy in a fertile female. In humans it accounts for 40-50% of infertility. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.-Pre-testicular... |
| Intoxications | asbestos Asbestos Asbestos is a set of six naturally occurring silicate minerals used commercially for their desirable physical properties. They all have in common their eponymous, asbestiform habit: long, thin fibrous crystals... , benzpyrene |
salts of Hg Mercury (element) Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum... and Cr Chromium Chromium is a chemical element which has the symbol Cr and atomic number 24. It is the first element in Group 6. It is a steely-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odorless, tasteless, and malleable... , ozone Ozone Ozone , or trioxygen, is a triatomic molecule, consisting of three oxygen atoms. It is an allotrope of oxygen that is much less stable than the diatomic allotrope... (O3) |
Mathematical models
Several mathematical models of chemotaxis were developed depending on the type of- migration (e.g. basic differences of bacterial swimming, movement of unicellular eukaryotes with cilia/flagellumFlagellumA flagellum is a tail-like projection that protrudes from the cell body of certain prokaryotic and eukaryotic cells, and plays the dual role of locomotion and sense organ, being sensitive to chemicals and temperatures outside the cell. There are some notable differences between prokaryotic and...
and ameboid migration); - physico-chemical characteristics of the chemicals (e.g. diffusionDiffusionMolecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
) working as ligands; - biological characteristics of the ligands (attractant, neutral and repellent molecules;
- assay systems applied to evaluate chemotaxis (see incubation times, development and stability of concentration gradients);
- other environmental effects possessing direct or indirect influence on the migration (lighting, temperature, magnetic fields etc.)
Although interactions of the factors listed above make the behavior of the solutions of mathematical models of chemotaxis rather complex, it is possible to describe the basic phenomenon of chemotaxis-driven motion in a straightforward way.
Indeed, let us denote with
the spatially non-uniform concentration of the chemo-attractant and with its gradient. Then the chemotactic cellular flow (also called current) that is generated by the chemotaxis is linked to the above gradient by the law: , where is the spatial density of the cells and is the so-called ’Chemotactic coefficient’. However, note that in many cases is not constant: it is, instead, a decreasing function of the concentration of the chemo-attractant : .In the mirror of publications
Research of cell migration–as it was shown in the chapter ’History of chemotaxis research’–requires complementary application of classic and modern techniques. The field provides the possibility to present novel and valuable data in the basic research as well as in applied sciences. In the last 20–25 years, due to the factors mentioned above, there was an increase in number of publicationPublication
To publish is to make content available to the public. While specific use of the term may vary among countries, it is usually applied to text, images, or other audio-visual content on any medium, including paper or electronic publishing forms such as websites, e-books, Compact Discs and MP3s...
s dealing with itself the phenomenon chemotaxis. Nevertheless, other publications written in genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
, biochemistry
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, cell-physiology, pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
and clinical sciences could also incorporate data about migration or especially the chemotaxis of cells. A curiosity of migration research is that among several works investigating taxes (e.g.thermotaxis
Thermotaxis
Thermotaxis is a behavior in which an organism directs its locomotion up or down a gradient of temperature.Lab research has determined that some slime molds and small nematodes can migrate along amazingly shallow temperature gradients of less than 0.1C/cm...
, geotaxis, phototaxis
Phototaxis
Phototaxis is a kind of taxis, or locomotory movement, that occurs when a whole organism moves in response to the stimulus of light. This is advantageous for phototrophic organisms as they can orient themselves most efficiently to receive light for photosynthesis...
) chemotaxis research shows a significantly high ratio, which point to the underlined importance of chemotaxis research both in biology
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
and medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
.
Measurement of chemotaxis
A wide range of techniques is available to evaluate chemotactic activity of cells or the chemoattractant and chemorepellent character of ligands.The basic requirements of the measurement are as follows:
- concentration gradients can develop relatively fast and persist for a long time in the system
- chemotactic and chemokinetic activities are distinguished
- migration of cells is free towards and away on the axis of the concentration gradient
- detected responses are the results of active migration of cells
Despite the fact that an ideal chemotaxis assay
Chemotaxis assay
Chemotaxis assays are experimental tools for evaluation of chemotactic ability of prokaryotic or eukaryotic cells.A wide variety of techniques are known and applied for such reason...
is still not available, there are several protocols and pieces of equipment which offer good correspondence with the conditions described above. The most commonly used are summarised in the table below:
| Type of assay | Agar-plate assays | Two-chamber assays | Others |
|---|---|---|---|
| Examples |
|
|
|
External links
- Chemotaxis (a book)
- Chemotaxis
- Neutrophil Chemotaxis
- Cell Migration Gateway
- Global Existence for Chemotaxis with Finite Sampling Radius
- Bacterial Chemotaxis Depends on a Two-Component Signaling Pathway Activated by Histidine-Kinase-associated Receptors, Molecular Biology of the Cell 4th Edition © 2002 by Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter.
- Figure 15-69. The two-component signaling pathway that enables chemotaxis receptors to control the flagellar motor during bacterial chemotaxis, Molecular Biology of the Cell 4th Edition © 2002 by Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter.
- Chemotaxis simulation downloadable from the Mathworks user-community, runs on Matlab
- Bacterial Chemotaxis Interactive Simulator - A web-app that features some simple algorithms for simulating bacterial chemotaxis.