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http://cro.sagepub.com/content/15/4/207The online version of this article can be found at:

 DOI: 10.1177/154411130401500404

2004 15: 207CROBMRenate Lux and Wenyuan Shi

Chemotaxis-guided Movements in Bacteria  

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15(4):207-220 (2004) Crit Rev Oral Biol Med 207

(1) Preface

The first observation of bacterial movement was made byAntony van Leeuwenkoek in 1683. While examining den-

tal plaque from the mouth of an old man, Leeuwenhoek found"an unbelievably great company of living animalcules, a-swimming more nimbly than any I had ever seen up to thistime. The biggest sort...bent their body into curves in goingforwards.... Moreover, the other animalcules were in suchenormous numbers, that all the water...seemed to be alive ...."(Fig. 1). Some of the bacteria described by van Leeuwenhoekare now recognized as the highly motile oral spirocheteswhose corkscrew-like motility results in a very remarkableswimming behavior that will be addressed in more detail later.

(2) Bacterial MovementSince van Leeuwenhoek's first report on bacterial motility, themajority of bacterial species were found to be motile during atleast a part of their life cycle (Fenchel, 2002). Bacterial motilitycan be categorized into flagellum-dependent motility and flagel-lum-independent motility. The flagellum is a bacterial motilityapparatus that, in most motile species, can be observed on thecell surface as long filamentous cellular appendices (Macnab,1996). The species variety within the bacterial kingdom is reflect-ed by an impressive diversity in flagellation patterns that com-monly serves as means of classification: Single or multiple fla-gella can be found at one cell pole (e.g., Helicobacter pylori,Pseudomonas sp., Vibrio sp., or Chromatium okenii), at both cellpoles (e.g., spirochetes or Spirillum sp.), in the middle of a cellbody (e.g., Rhodobacter spheroides or Selenomonas sp.), or all overthe cell body (Escherichia coli, Salmonella sp., or Bacillus subtilis).

While, for the most part, bacterial motility is associatedwith the presence of at least one flagellum, some bacteria dotranslocate without the aid of flagella. The best-studied flagel-lum-independent types of motility include the gliding motilityof myxobacteria, cyanobacteria, mycobacteria and theCytophaga-Flavobacterium group, the twitching motility ofPseudomonas, Neisseria, and Synechocystis (McBride, 2001), and

the swimming motility of Synechococcus (Ehlers et al., 1996).Flagellum-dependent motility, which generates bacterial

movement via rotation of the flagellar filaments in aquatic envi-ronments, has been extensively studied, revealing remarkableamounts of detailed structural and functional information(Macnab, 1996, 1999; Aldridge and Hughes, 2002). Much less isknown about flagellum-independent motility, which is mainlyinvolved in surface translocation. Recent studies suggest thatseveral independent mechanisms are involved (McBride, 2001;Bardy et al., 2003). Substantial evidence has been generated sup-porting a model for twitching motility of Pseudomonas aeruginosaand Neisseria gonorrhoeae as well as for cell-group gliding motil-ity of Myxococcus xanthus. In these species, movement is medi-ated through the extension, adherence, and retraction of type IVpili (Merz et al., 2000; Sun et al., 2000; Skerker and Berg, 2001; Liet al., 2003). It appears that the single-cell gliding motility ofcyanobacteria and myxobacteria is associated with secretion ofcarbohydrate containing slimes (Hoiczyk and Baumeister, 1995,1998; Wolgemuth et al., 2002). Surface translocation of the bacte-ria in the Cytophaga-Flavobacterium group may involve adher-ence of moving outer membrane components to the surface(Lapidus and Berg, 1982). However, various other motility mod-els—including wave generation in the outer membrane andmuscle-like expansion/contraction mechanisms—have beenproposed (Duxbury et al., 1980; Burchard, 1984). The glidingmotility of mycobacteria requires unique membrane proteinsthat modulate surface attachment/detachment by altering thehydrophobicity of the cell envelope (Recht et al., 2000), whereasthe swimming motility of Synechococcus appears to rely onstructures analogous to the cilia of eukaryotic organisms(Samuel et al., 2001).

(3) Bacterial ChemotaxisMore than two centuries after the detection of motile micro-organisms, Theodor Engelmann and Wilhelm Pfeffer foundthat bacterial movement was not random and arbitrary(Engelmann, 1883; Pfeffer, 1884). Instead, bacterial cells exhibit-

CHEMOTAXIS-GUIDED MOVEMENTS IN BACTERIA

Renate LuxWenyuan Shi*

School of Dentistry, Department of Microbiology, Immunology and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA 90095; *corresponding author, [email protected]

ABSTRACT: Motile bacteria often use sophisticated chemotaxis signaling systems to direct their movements. In general, bac-terial chemotactic signal transduction pathways have three basic elements: (1) signal reception by bacterial chemoreceptorslocated on the membrane; (2) signal transduction to relay the signals from membrane receptors to the motor; and (3) signaladaptation to desensitize the initial signal input. The chemotaxis proteins involved in these signal transduction pathways havebeen identified and extensively studied, especially in the enterobacteria Escherichia coli and Salmonella enterica serovar typhimuri-um. Chemotaxis-guided bacterial movements enable bacteria to adapt better to their natural habitats via moving toward favor-able conditions and away from hostile surroundings. A variety of oral microbes exhibits motility and chemotaxis, behaviors thatmay play important roles in bacterial survival and pathogenesis in the oral cavity.

Key words. Motility, chemotaxis, pathogenesis, oral bacteria.

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ed directed movement toward certain stimuli and away fromothers, a behavior they termed 'chemotaxis'. The discovery ofchemotaxis gave a completely new meaning to the ability ofbacteria to move within their environment. With the recogni-tion of chemotaxis-guided bacterial motility, it became appar-ent that bacteria can respond efficiently to environmentalchanges. Almost every motile bacterial species studied so farhas been found to possess chemotactic abilities which enablethem to adapt better to their natural habitats. For example, thetumor-inducing Agrobacterium tumefaciens enhances coloniza-tion by moving chemotactically toward injured plant rootsguided by specific phenolics released by the wound sites(Hawes and Smith, 1989; Shaw, 1991), Rhizobium sp. are attract-ed by substances exuded by plant roots during nodulation(Ames et al., 1980; Parke et al., 1985; Armitage et al., 1988;Pandya et al., 1999), Halobacterium sp. use phototaxis that is trig-gered by light of the wavelengths required for photosynthesis(Schimz and Hildebrand, 1979; Sundberg et al., 1990; Krohs,1994; Cercignani et al., 2000), and motile E. coli and Salmonellacells move toward optimal nutrients such as sugars, aminoacids, and oxygen (Stock and Surette, 1996). In addition toresponses to environmental signals, motility and chemotaxishave been found to be involved in virulence of many patho-genic bacteria (Freter, 1981; Ottemann and Miller, 1997; Lux etal., 2000; Josenhans and Suerbaum, 2002).

(4) Understanding the Molecular Mechanism of Chemotaxis

Since its discovery, chemotactic behavior has stimulated thecuriosity of numerous investigators. However, it wasn't untilthe groundbreaking work by Julius Adler—using genetic, bio-chemical, and behavioral approaches to analyze the chemotac-

tic behavior of E. coli—that a detailed understanding of thisphenomenon became possible (Adler, 1965, 1969, 1973, 1975;Armstrong et al., 1967; Armstrong and Adler, 1969a,b). Theintensive research efforts by numerous laboratories in the ensu-ing 40 years have yielded a comprehensive understanding ofthe molecular mechanism of bacterial chemotaxis. In general,the bacterial chemotactic signal transduction pathway hasthree basic elements (Fig. 2): (1) signal reception by bacterialchemoreceptors located on the membrane; (2) signal transduc-tion to relay the signals from membrane receptors to the motor;and (3) signal adaptation to desensitize the initial signal input.

(4.1) SIGNAL RECEPTION BY MEMBRANE RECEPTORS

Bacterial chemoreceptors are membrane proteins that can bemodified by methylation at specific glutamate and glutamineresidues, and are therefore also called methyl-accepting chemo-taxis proteins (MCPs) (Kort et al., 1975). MCPs are very sensi-tive detection devices that can perceive the extracellular con-centrations of specific ligands at low concentrations in the �Mto nM range (Clarke and Koshland, 1979; Biemann andKoshland, 1994; Lin et al., 1994). Most chemoreceptors bindonly a small number of specific ligands but do not transportthem. The occupancy with ligand is constantly monitored bythe cell and transformed into appropriate motor responses.Lack of a specific MCP does not affect the cell's general abilityto perform chemotaxis but only abolishes the response to thechemo-effectors perceived by the missing MCP (Adler, 1969).

Recently, it has become evident that bacterial chemorecep-tors are not isolated entities but rather function as 'signaling lat-tices' that facilitate 'teamworking' of various receptor types for

208 Crit Rev Oral Biol Med 15(4):207-220 (2004)

Figure 1. Original drawing from Antony van Leeuwenhoek's notes.Shown are some types of bacteria that he observed in a dentalplaque sample. Among them appear to be cocci (E), fusiforme bac-teria (F), and spirochetes (G)

Figure 2. Schematic illustration of basic chemotactic signal transduc-tion pathway. The proteins involved in the basic chemotactic signaltransduction pathway are shown. The excitation response involvessignal reception by the chemoreceptors (MCP) and further signaltransduction via CheW, CheA, and CheY to the flagella motor.Adaptation is achieved via methylation/demethylation of the MCPsby CheR and CheB. See text for details.

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stronger signal amplification (Ames et al., 2002; Gestwicki andKiessling, 2002). The individual receptor types form very stablehomodimers that are organized in higher-order structures ingroups of three (trimers of dimers) (Kim et al., 1999). These'trimers of dimers' tend to cluster in large patches at the cellpoles in a variety of bacteria (Alley et al., 1992; Maddock andShapiro, 1993; Harrison et al., 1999; Gestwicki et al., 2000). Thishigher-order clustering is thought to have an important biolog-ical role in signal amplification, since the clustered chemore-ceptors can sense very small changes in stimulus concentration(1-10%) that would otherwise not be detected (Mesibov et al.,1973; Jasuja et al., 1999; Kim et al., 2001). The clustering andpolar localization of the chemoreceptor that facilitates sensitiveresponses to small environmental changes is highly conservedamong bacteria. Phylogenetically very distant species like E.coli, B. subtilis, or Spirocheta aurantia exhibit very similar pat-terns (Lamanna et al., 2002).

A 'classic' chemoreceptor is a membrane-spanning proteinthat can be divided into three major parts: an 'extra-cytoplas-mic' ligand-binding domain and a transmembrane segmentthat connects to a cytoplasmic portion consisting of the signal-ing and methyl-accepting domains. The MCPs of E. coli and S.enterica serovar typhimurium have been intensively studied bygenetic, biochemical, and structural analysis techniques forseveral decades, and detailed structural and functional infor-mation has been revealed. Structural analysis uncovered amainly helical composition of the MCPs. X-ray crystallographyshowed that the periplasmic ligand-binding or sensory domainof the enteric chemoreceptors consists of a four-helix bundle(Fig. 3) (Milburn et al., 1991; Yeh et al., 1993). Two of thesehelices extend into the cytoplasmic membrane as the trans-membrane portion. Ligand-binding surfaces have been identi-fied via genetic mapping of the residues involved (Kossmann etal., 1988; Wolff and Parkinson, 1988; Mowbray and Koshland,1990; Gardina et al., 1992; Scott et al., 1993) and co-crystalizationof the ligand with the ligand-binding domain (Milburn et al.,1991). The structural changes that are induced upon ligand-binding to the sensory domain of the receptor and transmittedvia the transmembrane segment to the cytoplasmic domainhave been analyzed in great detail by solid-state nuclear mag-netic resonance (NMR) and spin-labeling electron paramagnet-ic resonance (EPR) techniques (Ottemann et al., 1998).

Recently, deviations from the 'standard' ligand-bindingdomain have been discovered in a variety of bacterial species:Caulobacter crescentus, R. spheroides, the archeon Halobacteriumsalinarium, B. subtilis, and possibly others that contain 'soluble'receptors missing the transmembrane part (Harrison et al.,1999; Larsen et al., 1999; Hou et al., 2000, 2001; Potocka et al.,2002; Wadhams et al., 2002). These receptors are membrane-associated or found in the cytoplasm rather than integratedinto the membrane. Interestingly, similar to myoglobin, the sol-uble chemoreceptors of H. salinarium and B. subtilis carry heme-groups in their sensory domains that allow for oxygen-bindingand are involved in aerotactic signaling.

The membrane-proximal part of the cytoplasmic domain,the so-called 'linker region', which consists of an extension ofone of the transmembrane helices, contains a motif thatappears to be highly conserved among signaling proteins inbacteria as well as in archaea (Aravind and Ponting, 1999;Galperin et al., 2001). This domain is a member of a newlyemerging family of signaling domains commonly found in var-ious signaling pathways, the HAMP domain (Aravind and

Ponting, 1999). A possible function of this domain may involvedimer formation. The remaining part of the cytoplasmicdomain is composed of two helices carrying conserved gluta-mine and glutamate residues that are required for the ability toadapt to a given chemo-effector concentration, a process thatwill be explained in section (4.3). The membrane-distal portionof the cytoplasmic chemoreceptor domain can bind the mainchemotaxis proteins CheA/CheW that relay the signal to themotor via the phosphotransfer reactions detailed below.

(4.2) SIGNAL RELAYFROM MEMBRANE RECEPTORS TO THE MOTOR

The environmental signal perceived by the chemoreceptorstriggers an excitation response that is relayed to the motor via acognate pair of bacterial sensory proteins, CheA (a histidinekinase) and CheY (a response regulator). Both proteins are rep-resentative members of the two-component-system super-fam-ily which executes most signal transduction events in bacteria(Stock et al., 2000; West and Stock, 2001). The histidine kinaseCheA forms a tight ternary complex with the cytoplasmic sig-naling domain of MCP in conjunction with the coupling factorCheW (Gegner et al., 1992; Boukhvalova et al., 2002). CheA hasbeen studied extensively, and many functional aspects are nowwell-understood (Stock and Surette, 1996; Stock et al., 2000). Incontrast, the exact function of CheW still remains largelyunknown, despite detailed genetic and structural analyses(Conley et al., 1989; Gegner and Dahlquist, 1991; Gegner et al.,1992; Griswold and Dahlquist, 2002; Griswold et al., 2002).

CheA autophosphorylates at a highly conserved histidineresidue with ATP as a substrate, after which the phosphorylgroup is transferred from CheA to a conserved aspartateresidue of its cognate response regulator CheY (Hess et al.,1988; Borkovich et al., 1989). In its phopshorylated state, CheYcan bind to the motor and reverse the direction of flagella rota-tion or modulate the speed of flagella rotation, depending onthe type of flagellated motility used by the individual species(Welch et al., 1993). Another cognate response regulator for

15(4):207-220 (2004) Crit Rev Oral Biol Med 209

Figure 3. Schematic illustration of chemoreceptor structure. The 'clas-sic' chemoreceptor consists of an extracytoplasmic (periplasmic) lig-and-binding domain and a transmembrane portion that connects tothe cytoplasmic domain via a HAMP domain. The cytoplasmicdomain contains the CheA/CheW binding domain and methylationsites that are substrate for CheR and CheB. See text for more details.

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CheA is the methylesterase/amidase CheB that is required foradaptation (Hess et al., 1988), which will be discussed later.

As mentioned earlier, conformational changes induced byligand-binding to the sensory domain of MCP are transmittedto the signaling domain and result in subsequent structuralchanges that control CheA autophosphorylation activity. Inmany species, the presence of a repellent (negative chemo-effectors) greatly stimulates CheA autophosphorylation,whereas attractant (positive chemo-effectors) binding to thechemoreceptor results in an almost complete shutdown ofautokinase activity (Borkovich et al., 1989; Simon et al., 1989;Ninfa et al., 1991).

Similar to the chemoreceptors, CheA of the model orga-nisms E. coli and S. enterica serovar typhimurium has been exten-sively characterized for more than two decades by genetic, bio-chemical, and structural approaches. CheA is a unique histi-dine kinase (Dutta et al., 1999) and can be divided into five dis-tinct functional domains (Fig. 4): the N-terminal phosphotrans-fer domain (HPt), the YB or S domain for response regulatorrecognition, a separate dimerization domain (unlike other his-tidine kinases), a catalytic kinase domain (CA), and the C-ter-minal receptor/CheW binding domain (R). Like all histidinekinases, CheA functions as a dimer, with the kinase domain ofone subunit phosphorylating the conserved histidine of theother and vice versa (Schuster et al., 1993; Swanson et al., 1993;Wolfe and Stewart, 1993).

The next interacting partner in the signal transductionchain of the excitation response is CheY, one of the cognateresponse regulators for CheA. CheY is an unusual responseregulator, since it consists only of the phosphorylatableresponse regulator domain but is lacking the DNA-bindingdomain or any other catalytic subunit that is characteristic ofthe majority of response regulators (Stock et al., 2000). CheYdirectly interacts with the switch protein, FliM, of the flagellarmotor and induces alterations in swimming behavior (Romanet al., 1992; Sockett et al., 1992). Upon CheY binding to the YBdomain of CheA, the phosphoryl group is transferred from theconserved histidine to the conserved aspartate of CheY (Hess etal., 1988; Wylie et al., 1988). Phosphorylation of CheY results ina conformational change that decreases its affinity for CheA(Schuster et al., 1993; Swanson et al., 1993) but increases its affin-

ity for the motor protein FliM (Welch et al., 1993). The release ofphosphorylated CheY from CheA and subsequent binding tothe motor switch is an important part in the signal transductionprocess.

Ultimately, the environmental signals perceived by thechemoreceptors are relayed to a motor to enable the organismto perform displacements corresponding to the type of stimu-lus perceived. The flagellar motor of the enteric bacteria E. coliand S. enterica serovar typhimurium has been studied in greatdetail for several decades (Fig. 5) (Macnab, 1996, 1999). As men-tioned earlier, flagella are thin helical cellular appendices thatcan be localized as a single structure or as a bundle at one orboth cell poles, evenly distributed over the cell surface, or evenreside in the periplasmic space (Eisenbach, 2000). Typically, thelong helical flagellum is connected to the membrane-integralbasal body that extends to a bell-shaped structure into the cyto-plasm via a curved hook (Macnab, 1996, 1999). This basal body,in combination with a ring of transmembrane stators formedby the MotA/B complexes (Khan et al., 1988), is thought to bethe rotary device that powers flagella rotation via H+ or Na+

gradients (Larsen et al., 1974; Manson et al., 1977; Shioi et al.,1978; Goulbourne and Greenberg, 1980; Imae et al., 1986;Kawagishi et al., 1995). Many flagellar motors are reversiblerotary devices whose direction of rotation is controlled by theintracellular ratio of CheY to CheY~P. Some motors, however,are unidirectional, and CheY~P binding modulates the speedrather than the direction of rotation (Gotz and Schmitt, 1987;Packer and Armitage, 1993; Platzer et al., 1997). In all these dif-ferent systems, the ratio of CheY to CheY~P is modulated bythe MCP/CheW/CheA/CheY signaling complex in accor-dance with the input signal (attractants or repellents).Depending on the input signal, MCPs will relay positive ornegative chemotactic signals, thus decreasing or increasingCheY~P levels.

The flagella motor is encoded by more than 50 genes that

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Figure 4. Schematic illustration of CheA domain organization. CheAis organized into five distict domains: (a) a phosphotransfer domain(HPt), a response regulator binding domain (YB), a dimerizationdomain (D), a catalytic kinase domain (CA), and a chemorecep-tor/CheW binding domain (R). (b) CheA forms a homodimer withthe two subunits phosphorylating each other. Figure 5. Schematic illustration of flagella motor. The basic elements

of the flagella rotary motor are shown. The basal body is formed bythe membrane integral M/S-ring and its cytoplasmic extension, theC-ring, and connects via a curved hook to the flagellum. These partsare thought to comprise the rotary part of the flagella motor. Themembrane-spanning Mot complexes build the stator that allows fortorque generation. For more detailed information on architecture andfunction, see Macnab (1996, 1999).

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are expressed following a strictly controlled hierarchy to ensureproper assembly of this complex structure (Macnab, 1996; Kaliret al., 2001). In E. coli and S. enterica serovar typhimurium, a mas-ter operon on top of this hierarchy is absolutely necessary forexpression of the remainder of the flagellum-related genes thatare organized into 15 and 17 operons, respectively (Komeda etal., 1980; Kutsukake et al., 1988).

(4.3) SENSORY ADAPTATION AND DESENSITIZATION

Sensory adaptation (or desensitization) describes the ability ofan organism to re-set and desensitize its signal transductionsystem to the original stimulus. This important feature allowsthe organism to respond to higher concentrations of the samechemo-effectors or other types of chemo-effectors. Adaptationis a time-delayed secondary mechanism that sets in after theexcitation response is accomplished. The 'excited' chemorecep-tors are desensitized via reversible methylation events of theircytoplasmic signaling domain (Springer et al., 1979). Binding ofan attractant results in increased methylation levels, whereasdemethylation occurs when the ligand is a repellent. Theseactions are performed by two enzymes: CheR, a methyltrans-ferase (Springer and Koshland, 1977; Simms et al., 1987;Djordjevic and Stock, 1997); and CheB, which exhibits deami-dase as well as methylesterase activity (Stock and Koshland,1978; Djordjevic et al., 1998) (Fig. 2). Substrates for theseenzymes are conserved glutamate and glutamine residueswithin the signaling domain of MCP that regulates CheA activ-ity (Stock and Surette, 1996). The glutamine residues requiredeamidation (to glutamate) by CheB to become a substrate formethylation by CheR in a S-adenosyl-methionine-dependentreaction (Rollins and Dahlquist, 1981; Sherris and Parkinson,1981). Upon methylation of these sites, the signaling domain ofMCP activates CheA autokinase activity similarly to the struc-tural changes induced by repellent binding to the ligand-bind-ing domain of the chemoreceptor (Ninfa et al., 1991; Borkovichet al., 1992). Demethylation by the CheR-antagonist, CheB(Simms et al., 1987), has the opposite effect.

These chemo-effector-specific shifts in chemoreceptormethylation levels are achieved by the regulatory and catalyticproperties of CheR and CheB: The methyltransferase CheRmethylates the chemoreceptor cytoplasmic domain with a con-stant slow turnover rate of about 6 min-1 and does not appearto be regulated (Simms et al., 1987). The methylesterase activityof the catalytic domain of CheB, in contrast, is strictly con-trolled by its regulatory domain (Hess et al., 1988; Lupas andStock, 1989; Stewart et al., 1990). As mentioned earlier, similarto CheY, CheB constitutes a cognate response regulator forCheA. The methylesterase activity of CheB is regulated accord-ing to the autophosphorylation levels of its histidine kinase(Hess et al., 1988; Lupas and Stock, 1989; Stewart et al., 1990)and exhibits a strong intrinsic autophosphatase activity (Lukatet al., 1991; Stewart, 1993). CheB activity increases over 10-foldupon phosphorylation with a basal level of activity in theunphosphorylated protein below the CheR methyltransferaserate (Hess et al., 1988; Lupas and Stock, 1989; Stewart et al.,1990). Both CheB and CheR were found to be intimately asso-ciated with the ternary signaling complex (MCP, CheA, andCheW) (Wu et al., 1996; Djordjevic and Stock, 1998b), and theirrespective structures have been solved (Djordjevic and Stock,1997, 1998a,b; Djordjevic et al., 1998). In an unstimulated cell,both enzymes maintain an equilibrium of methylation/de-methylation.

In brief, adaptation to a chemo-effector (e.g., an attractant)involves the following scenario: During the excitation response(signal reception and signal transduction), the binding ofattractant molecules to the MCPs abolishes the autokinaseactivity of CheA completely, triggering a smooth swimmingresponse of the cell as a result of decreasing CheY~P levels.Simultaneously, phosphorylation levels of CheB, the other cog-nate response regulator of CheA, decrease as well, resulting inlow CheB methylesterase activity. In the meantime, CheR,whose activity appears not to be regulated, keeps addingmethyl groups to the cytoplasmic portion of the MCP. Thiscombination of reduced CheB activity and constant CheR-mediated methylation leads to a shift of the methylation equi-librium in the chemoreceptors of an unstimulated cell towardthe methylated state. Chemoreceptor methylation overrides thestructural changes in the signaling domain that originallycaused the inhibition of CheA activity. As a result, CheA auto-phosphorylation increases to pre-stimulation levels. The phos-phorylation levels of CheY and CheB rise as well, and the celleventually balances its behavior to an unstimulated randomwalk, even in the presence of an attractant. Adaptation to repel-lents involves opposite changes in activity and chemoreceptormethylation levels.

In some bacterial species, including the enteric bacteria E.coli and S. enterica serovar typhimurium, adaptation is enhancedby a CheY-specific phosphatase, CheZ (Hess et al., 1988).However, most bacterial species do not contain this protein andhave evolved other strategies, such as using additional CheY-homologues as a phosphate sink (see section 4.4) (Armitageand Schmitt, 1997) or requiring only the action of CheB andCheR for adequate adaptation.

In summary, during chemotaxis of E. coli and S. entericaserovar typhimurium (the enterobacterial paradigm), environ-mental gradients are perceived by (typically transmembrane)chemoreceptors that form a complex with the protein kinaseCheA via the coupling protein CheW. CheA autophosphory-lates itself at a histidine residue with ATP as a substrate and isable to transfer this phosphor group to a highly conservedaspartate in CheY. CheY is a small protein that can freely dif-fuse in the cell, binds to a motor switch upon phosphorylation,and modulates the bacterial swimming behavior according tothe stimulus detected. The phosphorylation level of CheY ulti-mately determines the motor response. Attractant binding sup-presses CheA autophosporylation, resulting in a smooth swim-ming behavior, whereas repellents greatly stimulate autophos-phorylation of this protein, and the subsequent rise in intracel-lular CheY~P levels causes the cells to tumble. Adaptation tosuch stimuli involves methylation and demethylation eventsthat are carried out by the methylase CheR and themethylesterase CheB, another cognate response regulator forCheA.

(4.4) VARIATIONS OF THEENTEROBACTERIAL PARADIGM

The chemotaxis in E. coli and S. enterica serovar typhimuriumhas been intensely investigated for several decades, providingvery detailed understanding of many of the underlying mech-anisms. Since these two species have been the focus of chemo-taxis research for so long, they eventually became the 'para-digm' for bacterial chemotaxis. Initially, other bacterialspecies—such as B. subtilis or R. spheroides—that were cominginto play but would not 'follow the rules' were regarded some-

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what as oddballs in the swimming world. With more and moredifferent bacterial species studied outside of the enteric world,and especially with genome information becoming available atan almost exponential rate over the past couple of years, it hasbecome apparent that even though the basic mechanisms out-lined earlier are highly conserved, the variations on the themeare manifold and could be the rule rather than the exception.

Unique chemotaxis proteins are found in the spirochetesthat contain some members of the oral community in the formof oral treponemes. The chemotaxis operons of spirochetes con-tain a novel gene cheX in addition to cheA and cheY, as well asan interesting gene fusion between cheW and cheR (Greene andStamm, 1999). CheX is required for chemotaxis, since cheX geneinactivation mutants fail to respond to chemo-effectors (Lux etal., unpublished results). A possible role in controlling cellularreversal has been implied. Homologues of cheX can be found inother bacterial genomes, but they are not localized in chemo-taxis operons. Since functional studies of this protein in bacte-ria other than the spirochetes Treponema denticola and Borreliaburgdorferi are still lacking, its general function in other speciesremains unclear.

So far, the Gram-positive soil bacterium B. subtilis seems tocontain the most novel or unusual chemotaxis proteins besidesthe chemoreceptors and the proteins CheA, CheW, and CheY,that form the backbone of the general chemotactic signal trans-duction pathway. Interestingly, in this bacterium, the defaultrotation of its motor causes tumbling rather than the smoothswimming behavior observed in many other bacterial species(Garrity and Ordal, 1995). Chemotaxis genes that are requiredfor proper function of the chemotaxis pathway in B. subtilis butdo not have counterparts in the E. coli genome are comprised ofcheC, cheD, and cheV. All three proteins (CheC, CheD, andCheV) appear to be involved in particular aspects of adaptationto specific attractant stimuli (Rosario and Ordal, 1996; Zimmeret al., 2000; Karatan et al., 2001; Kirby et al., 2001; Kristich andOrdal, 2002) and are needed in addition to CheB and CheR,which are known to mediate adaptation (Kirsch et al., 1993a,b).CheC has been found to interact with McpB and CheA of theternary signaling complex, CheD, and the motor protein FliY.CheC action appears to be involved in the regulation ofchemoreceptor methylation in combination with CheD by anunknown mechanism. This protein possibly shuttles betweenthe input (ternary complex of MCP, CheA, and CheW) and out-put (motor) domains of the excitation pathway to relay adap-tation events. Despite extensive genetic analysis that revealedan array of distinct phenotypes, no specific functional mecha-nism has been found so far for this protein; therefore, the exactrole of CheC in adaptation remains speculative. In addition toits role in receptor methylation, CheD is thought to facilitateCheA autophosphorylation, even though a direct interactionbetween these two proteins was not observed (Kristich andOrdal, 2002). CheV exhibits strong homology to CheW at its N-terminus and contains a response-regulator domain at the C-terminal portion (Rosario et al., 1994). This protein was recent-ly found to be required for adaptation to specific amino acidsand appears to be activated upon phosphorylation by CheA,thus constituting a third cognate response regulator for thisautokinase (Karatan et al., 2001). Mutant strains defective inCheV phosphorylation or lacking the protein still showed nor-mal excitation responses but were missing adaptation to certainstimuli.

Another well-studied example of 'variation of the entero-

bacterial paradigm' is the soil bacterium, Sinorhizobium meliloti.Unlike B. subtilis or the spirochetes, this member of the �-sub-class of proteobacteria does not contain any novel chemotaxisproteins, but does contain the same linear excitation pathwayknown for E. coli and S. enterica serovar typhimurium. S. melilotilacks the phosphatase CheZ but features a second CheY homo-logue (Greck et al., 1995; Sourjik and Schmitt, 1996). This CheYhomologue is not involved in the excitation pathway but servesas a phosphate sink, thus substituting for CheZ function(Sourjik and Schmitt, 1998). Interestingly, many motile mem-bers of the same subclass of proteobacteria—including R. spher-oides, C. crescentus, and A. tumefaciens—appear to feature a sim-ilar 'phosphate sink' mechanism, since they encode homo-logues of this cheY pair while lacking cheZ (Armitage andSchmitt, 1997). In addition to CheY homologues that may serveas a phosphate sink rather than transducing the excitationresponse, R. spheroides contains multiple complete chemotaxispathways, including 13 chemoreceptors, four CheW, fourCheA, six CheY, two CheB, and three cheR homologues, mostof which are essential for normal chemotaxis responses (Martinet al., 2001). Recent evidence suggests that these pathways arenot independent of each other, but instead, are interconnectedin a very complex signaling network whose detailed interac-tions remain to be elucidated (Porter and Armitage, 2002).

(5) The Role of Motility and Chemotaxis in Microbial Pathogenesis

Tested with in vivo pathogenesis model systems, many motilepathogens were found to require their flagella and, in manycases, normal motility for efficient infection (Ottemann andMiller, 1997; Josenhans and Suerbaum, 2002). Interestingly, avariety of these organisms also exhibit a striking co-regulationof motility/chemotaxis genes and virulence factors, underscor-ing the in vivo significance of (directed) movement during var-ious stages of the infectious process (Akerley et al., 1992, 1995;Givaudan and Lanois, 2000; Hay et al., 1997; Lee et al., 2001;Sperandio et al., 2001; Krukonis and DiRita, 2003; Liaw et al.,2003; Xu et al., 2003). More than two decades ago, chemotaxisas the navigation system for motility had already been contem-plated to be an important feature for the virulence of manymotile pathogens (Freter, 1981; Freter et al., 1981a,b; Freter andO'Brien, 1981a,b). Until very recently, however, little attentionhas generally been paid to this interesting idea compared withthat devoted to the emerging studies on the involvement ofmotility in pathogenesis.

For important pathogens such as H. pylori (the primarycausative agent of chronic gastric diseases) or Campylobacterjejuni (one of the major factors in food-borne diseases), the sig-nificance of chemotaxis for pathogenesis in addition to motili-ty has been established (Takata et al., 1992; Yao et al., 1997;Foynes et al., 2000). Mutant strains lacking the central proteinsof the chemotaxis pathway, CheA or CheY, failed to colonizethe gastric/intestinal mucus layer of their host successfully invivo and establish infection. Recently, two chemoreceptors werefound to promote H. pylori-induced stomach infection(Nakazawa, 2002). Both H. pylori (Foynes et al., 2000) and C.jejuni (Hugdahl et al., 1988) are known to perform chemotaxistoward components present in mucin, which could play a rolein identifying suitable colonization sites (Nakazawa, 2002).Similarly, chemotactic motility toward mucin was shown to beindispensable for the fish pathogen Vibrio anguillarum to initiateinfection in its host (O'Toole et al., 1996, 1999). Other mucus

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chemotaxis-associated infections with V. cholerae andBrachyspira (Serpulina) hyodysenteriae have also been reported(Freter et al., 1981b; Freter and O'Brien, 1981b; Kennedy andYancey, 1996). Recent studies in V. cholerae revealed that eventhough mutants defective in chemotaxis were more successfulin colonization than the wild-type parent, the colonization pat-tern was erratic and spread throughout most of the gastro-intestinal tract, whereas the wild-type settles in specific parts ofthe small intestines (Lee et al., 2001). The same group alsofound that chemotaxis genes are the main regulators of choleratoxin production in vivo (Merrell et al., 2002); mutants lackingchemotaxis genes do not produce the toxins that trigger the dis-ease. Interestingly, V. cholerae, which is shed from the humanhost, was found to suppress chemotaxis gene expression. Basedon the above findings and earlier data by Freter and O'Brien(1981b), these authors then proposed a model whereby chemo-taxis might be important in the early stages of infection toguide the bacterium to a suitable niche within its host andinduce optimal virulence gene expression. Later, chemotaxisgene expression is down-regulated to produce motile but non-chemotactic cells that can easily be shed from the host and re-enter the infectious cycle.

The most controversial observations on the significance ofmotility and chemotaxis for virulence have been reported forthe enterobacterium S. enterica serotype typhimurium.'Salmonellosis' is one of the most widespread gastro-intestinalinfections and the second most common food-borne illness.Some authors claimed that the presence of flagella was not nec-essary for virulence (Lockman and Curtiss, 1990), or that fla-gella served only as an anchor for attachment but not as meansof locomotion during the pathogenic events (Carsiotis et al.,1984). Most investigators, though, acknowledged the impor-tance of flagellar motility for in vivo infection and recognizedthat motility did enhance the invasion process in in vitro animalmodel systems. Chemotaxis, however, was either notaddressed in these studies (Betts and Finlay, 1992; Lee et al.,1996; Methner and Barrow, 1997) or was found to be unneces-sary (Carsiotis et al., 1984). Some chemotaxis mutants thatresult in constantly smooth-swimming phenotypes were moreinvasive than wild-type mutants, whereas constantly tumblingderivatives exhibited a pronounced decrease in tissue invasive-ness, suggesting that the physical orientation of the flagella isimportant for the invasion process (Jones et al., 1992). Mostrecently, one group provided evidence that both motile andchemotaxis mutants failed to colonize successfully in an animalmodel (Lovell and Barrow, 1999). Additionally, co-regulation ofmotility and virulence genes has been described (Lucas et al.,2000).

P. aeruginosa is a bacterium that exhibits flagellated as wellas type IV pilus-dependent motility. It is an important oppor-tunistic pathogen that causes chronic pulmonary infections inabout 70% of patients with cystic fibrosis and in immuno-com-promised hosts. Colonization of P. aeruginosa on the mucus sur-face requires flagella and type IV pili. Chemotaxis of P. aerugi-nosa toward mucin has been found (Nelson et al., 1990) and wasshown to be involved in the initial stages of infection (Feldmanet al., 1998).

In addition to the above-mentioned gastro-intestinalpathogen B. hyodysenteriae that causes infections via intimateattachment to mucosal surfaces, many spirochetes are highlyvirulent or at least opportunistically pathogenic (Lux et al.,2000). Direct in vivo evidence demonstrating the involvement

of chemotaxis in the pathogenic process of these bacteria is stilllacking, but motility has been shown to be a crucial virulencefactor in vivo and in vitro (Sadziene et al., 1991; Lux et al., 2001).Most of these pathogenic spirochetes were also found to exhib-it strong chemotaxis responses toward substances that theywould encounter during infection of their respective hosts: B.burgdorferi, the causative agent for Lyme disease, has a life cycleinvolving persistence in the gut of ticks and entry into thebloodstream of their prospective mammalian hosts via the sali-vary glands of the tick. A study showed that the bacterium per-ceives salivary gland extract and serum as attractants (Shih etal., 2002). Other examples are that Leptospira interrogans per-forms chemotaxis toward hemoglobin, and that the oral spiro-chete T. denticola performs chemotaxis to serum and a variety ofsugars and amino acids (Mayo et al., 1990; Yuri et al., 1993;Kataoka et al., 1997; Li et al., 1999) and requires motility andchemotaxis for effective tissue penetration in vitro (Lux et al.,2001).

Bacteria that use chemotaxis and motility in their patho-genic processes also include some important plant pathogenssuch as A. tumefaciens or P. fluorescens (Hawes and Smith, 1989;Shaw, 1991; Singh and Arora, 2001; de Weert et al., 2002).Symbiotic events between Rhizobium sp. or Azospirillumbrasilense and their respective hosts rely equally on motility andchemotaxis (Schmidt, 1979; Gulash et al., 1984; Parke et al., 1985;Caetano-Anolles et al., 1988; Bakanchikova et al., 1989; VandeBroek et al., 1998; Pandya et al., 1999; ).

(6) Motility and Chemotaxis in Oral Bacteriaand Their Possible Roles in Pathogenesis

The most striking type of motility that can be observed in bac-terial plaque samples is without a doubt the corkscrew-likemovement exhibited by the oral spirochetes. More than 50 dif-ferent species of these interesting micro-organisms have beenidentified in the oral cavity, and all were found to be membersof the genus Treponema (Paster et al., 2002), although most ofthem cannot be cultivated in vitro for further analyses. The fla-gellated motility of spirochetes is unique, since the flagella donot extend as cellular appendices from their very long and thincell bodies but rotate within the periplasmic space. Similar tothe sheathed flagella of H. pylori (Geis et al., 1989), this interest-ing feature enables rapid motility to occur in very viscous gel-like environments (Charon et al., 1992b; Li et al., 2000) whererotation of unprotected external flagella is greatly impaired(Schneider and Doetsch, 1974). For example, T. denticola, themodel oral spirochete, increases its swimming velocities fromless than 5 �m/sec to up to 19 �m/sec in response to increasedviscosity and temperature (Ruby and Charon, 1998). Earliermeasurement by other investigators demonstrated a significantincrease of translocational speed under higher viscosity condi-tions, but the velocity reported was in the range of 19 µm/min(Klitorinos et al., 1993). The subpolar flagella at both cell endsrotate around the cell bodies to generate translocation. Thismovement of the flagella around the helical cytoplasmic cylin-der creates the thrust for the bacterium to swim through itsenvironment (Berg, 1976; Charon et al., 1992b). The motility pat-tern of spirochetes involves translocation in one direction thatcan be reversed, as well as an occasional bending of the cell inthe middle of its body, the so-called 'flexing' (Fosnaugh andGreenberg, 1988). Models explaining how flagellar rotation atopposing cell ends can result in unidirectional movement havebeen proposed for various spirochete species, including the

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human pathogens L. interrogans and B. burgdorferi, as well asthe free-living bacterium S. aurantia (Berg, 1976; Fosnaugh andGreenberg, 1988; Goldstein et al., 1994). As in most other free-swimming bacteria, the flagella motor is driven by protonmotive force (Goulbourne and Greenberg, 1980), and the direc-tion of flagellar rotation appears to be bi-directional, as foundin the enteric bacteria (Berg and Anderson, 1973; Charon et al.,1992a). The flagellar components of numerous spirochetes,including the oral spirochete T. denticola, are encoded by vari-ous gene clusters with strong homology to motility genes ofother motile organisms (Stamm and Bergen, 1999, 2001; Charonand Goldstein, 2002).

Treponemes have been associated early on with the etiolo-gy of periodontal disease, since they were always found in inti-mate association with inflamed gingival epithelium andappeared to be the only bacteria capable of penetration into thetissue (Listgarten et al., 1975; Soames and Davies, 1975). Thispredominance of oral spirochetes (in combination with fusifor-men bacteria) within diseased sites is especially pronounced inpatients with acute necrotizing ulcerative gingivitis (ANUG)(Rosebury and Sonnerwirth, 1958; Listgarten, 1965; Listgartenand Lewis, 1967; Loesche et al., 1982). Interestingly, Loesche(1976) hypothesized that nutrients present in the serum transu-date of the gingival crevice may attract the motile spirochetesand place them at the advancing margin of the plaque in thesubgingival sulcus. Later, the oral treponemes T. denticola, T.medium, and T. vincentii were actually found to perform chemo-taxis toward different sera, including rabbit, goat, horse,bovine, and human (Umemoto et al., 2001). Interestingly, T. den-ticola, which has been implicated as one of the causative agentsfor periodontal disease, exhibited the strongest response to alltypes of serum, whereas T. medium and T. vincentii were signif-icantly attracted only by rabbit serum. The active component in

serum was identified as albumin. Another study showed thatT. denticola is also attracted by a variety of sugars and aminoacids (Mayo et al., 1990). The chemotaxis response to serum andalbumin by treponemes could indicate the role of chemotaxis inthe pathogenesis of periodontal disease, since these compo-nents are exuded from the gingival crevice and could attracttreponemes to gingival pockets for colonization and initiationof periodontal disease.

Versatile genetic tools have recently become available for T.denticola, allowing for a more detailed examination of motilityand chemotaxis and their potential role in pathogenesis (Gironset al., 2000; Hardham and Rosey, 2000; Tilly et al., 2000). In addi-tion to the above-mentioned motility genes, an operon encod-ing the general chemotaxis genes cheA, cheW, the novel chemo-taxis gene cheX, and cheY, as well as two genes that exhibitstrong homology to known chemoreceptors, has been found inT. denticola (Kataoka et al., 1997; Li et al., 1999; Greene andStamm, 1999). Further genome search of the unfinished T. den-ticola genome database (www.tigr.org) revealed the presence ofabout 16 additional putative chemoreceptors and homologuesfor cheB and cheR (Lux and Shi, unpublished results). Thus, T.denticola has the complete set of chemotaxis genes required forsignal reception, transduction, and adaptation. Gene inactiva-tion of these chemotaxis genes results in loss of chemotacticresponses and altered motility patterns (Lux et al., 2002; Luxand Shi, unpublished results), indicating that these are indeedthe chemotaxis genes. Most interestingly, these chemotaxismutants are deficient in penetration of in vitro tissue layersformed by human gingival keratinocytes (Lux et al., 2001). Invitro tissue penetration has been established as a model systemfor assessment of the ability of pathogenic spirochetes tomigrate through endothelial or epithelial barriers (Thomas etal., 1988, 1989; Comstock and Thomas, 1989, 1991; Riviere et al.,1989, 1991; Szczepanski et al., 1990; Thomas and Higbie, 1990;Sadziene et al., 1991; Haake and Lovett, 1994; Peters et al., 1999;Lux et al., 2001). Strains unable to penetrate these in vitro tissueswere generally found to be non-virulent as well.

In addition to T. denticola, many other motile oral bacteria(Table)—including species of Campylobacter (Wolinella),Selenomonas, and Capnocytophaga—were frequently isolatedfrom the deep pockets of patients with aggressive forms ofperiodontal disease (Socransky, 1977; Slots, 1979; Tanner et al.,1979). The chemotactic properties of several oral Campylobacter(Wolinella) species have been compared with those of non-oralmembers of the same genus (Paster and Gibbons, 1986). Theoral Campylobacter strains were found to be strongly attractedby formate at concentrations similar to those measured in den-tal plaque (Gilmour et al., 1976), whereas intestinal species didnot perceive formate as a stimulus. Unidentified motile speciesisolated from dental plaque were also found to perceive for-mate, lactate, and n-valeric acid as positive chemo-effectors(Paster and Gibbons, 1986). The authors proposed that theobserved chemotaxis response toward these microbial metabo-lites would allow motile oral species to identify suitable colo-nization sites in periodontal pockets by localizing already-established microbial communities.

(7) Concluding RemarksMotility/chemotaxis is a very important feature that allowsbacteria to identify optimal growth conditions, avoid harmfulsituations, or target specific tissues for interaction or invasionof a host. Even though a vast amount of information leading to

214 Crit Rev Oral Biol Med 15(4):207-220 (2004)

TABLE

Representative Motile Bacteria in Oral Cavity

Type of Motility Genus Representative Oral Species

Flagellated Campylobacter concisus(Wolinella) curvae

rectusshowae

Centipeda periodontiiDesulfomicrobium oraleDesulfovibrioSelenomonas artemidis

flueggiiinfelixnoxiasputigena

Treponema denticolalecithinolyticummaltophilummediumsocranskiivincentii

Type IV pilus Eikenella corrodensMoraxella catarrhalis

Gliding Capnocytophaga

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detailed understanding of motility and chemotaxis at a molec-ular level has been collected for many bacterial species, stillvery little is known about these features in oral bacteria.Pioneering studies indicate that motility and chemotaxis mayassist oral bacteria to survive the complex oral flora environ-ment better, e.g., via directing the bacteria to favorable colo-nization sites for nutrition or to damaged tissue areas for inva-sion. With dental and periodontal disease still affecting themajority of the population worldwide, a more in-depth under-standing of the role of motility and chemotaxis in pathogenesisof oral bacteria may further our understanding of pathogenicevents in the oral cavity.

AcknowledgmentsWe gratefully acknowledge the critical comments and valuable advice of Drs.

Fengxia Qi, Melissa Sondej, and Richard Ellen. The review was prepared with

funding support from the National Institutes of Health, Washington Dental

Service, C3 Scientific Corporation, and BioSTAR of the University of

California.

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