Aggregatibacter actinomycetemcomitans is a Gram-negative bacterium that colonizes the human oral cavity and is the causative agent for localized aggressive periodontitis (LAP), an aggressive form of periodontal disease that occurs in adolescents. A. actinomycetemcomitans secretes a protein toxin, leukotoxin (LtxA), which helps the bacterium evade the host immune response during infection. LtxA is a membrane-active toxin that specifically targets white blood cells (WBCs). In this review, we discuss recent developments in this field, including the identification and characterization of genes and proteins involved in secretion, regulation of LtxA, biosynthesis, newly described activities of LtxA, and how LtxA may be used as a therapy for the treatment of diseases.
Avila-CamposMJ (1995). Haemolytic activity of Actinobacillus actinomycetemcomitans strains on different blood types. Rev Inst Med Trop São Paulo37:215-217.
2.
BaehniPTsaiCCMcArthurWPHammondBFTaichmanNS (1979). Interaction of inflammatory cells and oral microorganisms. VIII. Detection of leukotoxic activity of a plaque-derived Gram-negative microorganism. Infect Immun24:233-243.
3.
BaehniPCTsaiCCMcArthurWPHammondBFShenkerBJTaichmanNS (1981). Leukotoxic activity in different strains of the bacterium Actinobacillus actinomycetemcomitans isolated from juvenile periodontitis in man. Arch Oral Biol26:671-676.
4.
BakerPJHoweLGarneauJRoopenianDC (2002). T cell knockout mice have diminished alveolar bone loss after oral infection with Porphyromonas gingivalis. FEMS Immunol Med Microbiol34:45-50.
BalashovaNVDiazRBalashovSVCrosbyJAKachlanySC (2006b). Regulation of Aggregatibacter (Actinobacillus) actinomycetemcomitans leukotoxin secretion by iron. J Bacteriol188:8658-8661.
7.
BalashovaNVParkDHPatelJKFigurskiDHKachlanySC (2007). Interaction between leukotoxin and Cu, Zn superoxide dismutase in Aggregatibacter actinomycetemcomitans. Infect Immun75:4490-4497.
8.
BalashovaNVShahCPatelJKMegallaSKachlanySC (2009). Aggregatibacter actinomycetemcomitans LtxC is required for leukotoxin activity and initial interaction between toxin and host cells. Gene443:42-47.
9.
BalsalobreCSilvanJMBerglundSMizunoeYUhlinBEWaiSN (2006). Release of the type I secreted alpha-haemolysin via outer membrane vesicles from Escherichia coli. Mol Microbiol59:99-112.
10.
BaumannUWuSFlahertyKMMcKayDB (1993). Three-dimensional structure of the alkaline protease of Pseudomonas aeruginosa: a two-domain protein with a calcium binding parallel beta roll motif. EMBO J12:3357-3364.
11.
BechterOEEistererWDirnhoferSPallGKuhrTStauderR. (1999). Expression of LFA-1 identifies different prognostic subgroups in patients with advanced follicle center lymphoma (FCL). Leuk Res23:483-488.
12.
BeckJDEkePHeissGMadianosPCouperDLinD. (2005). Periodontal disease and coronary heart disease: a reappraisal of the exposure. Circulation112:19-24.
13.
BergeyDHHoltJG (1994). Bergey’s manual of determinative bacteriology. 9th ed.Baltimore, MD, USA: Lippincot, Williams & Wilkins.
14.
BertholdPFortiDKiebaIRRosenbloomJTaichmanNSLallyET (1992). Electron immunocytochemical localization of Actinobacillus actinomycetemcomitans leukotoxin. Oral Microbiol Immunol7:24-27.
15.
BhakdiSMartinE (1991). Superoxide generation by human neutrophils induced by low doses of Escherichia coli hemolysin. Infect Immun59:2955-2962.
16.
BroganJMLallyETPoulsenKKilianMDemuthDR (1994). Regulation of Actinobacillus actinomycetemcomitans leukotoxin expression: analysis of the promoter regions of leukotoxic and minimally leukotoxic strains. Infect Immun62:501-508.
17.
CrosbyJAKachlanySC (2007). TdeA, a TolC-like protein required for toxin and drug export in Aggregatibacter (Actinobacillus) actinomycetemcomitans. Gene388:83-92.
18.
DasMBadleyADCockerillFRSteckelbergJMWilsonWR (1997). Infective endocarditis caused by HACEK microorganisms. Annu Rev Med48:25-33.
19.
DiazRGhofailyLAPatelJBalashovaNVFreitasACLabibI. (2006). Characterization of leukotoxin from a clinical strain of Actinobacillus actinomycetemcomitans. Microb Pathog40:48-55.
20.
DileepanTKachlanySCBalashovaNVPatelJMaheswaranSK (2007). Human CD18 is the functional receptor for Aggregatibacter actinomycetemcomitans leukotoxin. Infect Immun75:4851-4856.
21.
DuvicMKuzelTMOlsenEAMartinAGFossFMKimYH. (2002). Quality-of-life improvements in cutaneous T-cell lymphoma patients treated with denileukin diftitox (ONTAK). Clin Lymphoma2:222-228.
22.
EvansRTKlausenBRamamurthyNSGolubLMSfintescuCGencoRJ (1992). Periodontopathic potential of two strains of Porphyromonas gingivalis in gnotobiotic rats. Arch Oral Biol37:813-819.
23.
FineDHKaplanJBKachlanySCSchreinerHC (2006). How we got attached to Actinobacillus actinomycetemcomitans: a model for infectious diseases. Periodontol 200042:114-157.
24.
FineDHMarkowitzKFurgangDFairlieKFerrandizJNasriC. (2007). Aggregatibacter actinomycetemcomitans and its relationship to initiation of localized aggressive periodontitis: longitudinal cohort study of initially healthy adolescents. J Clin Microbiol45:3859-3869.
25.
FletcherJMNairSPWardJMHendersonBWilsonM (2001). Analysis of the effect of changing environmental conditions on the expression patterns of exported surface-associated proteins of the oral pathogen Actinobacillus actinomycetemcomitans. Microb Pathog30:359-368.
26.
FongKPChungWOLamontRJDemuthDR (2001). Intra- and interspecies regulation of gene expression by Actinobacillus actinomycetemcomitans LuxS. Infect Immun69:7625-7634.
GallantCVSedicMChicoineEARuizTMintzKP (2008). Membrane morphology and leukotoxin secretion are associated with a novel membrane protein of Aggregatibacter actinomycetemcomitans. J Bacteriol190:5972-5980.
29.
GravesDTFineDTengYTVan DykeTEHajishengallisG (2008). The use of rodent models to investigate host-bacteria interactions related to periodontal diseases. J Clin Periodontol35:89-105.
30.
GuthmillerJMKolodrubetzDCagleMPKraigE (1990a). Sequence of the lktB gene from Actinobacillus actinomycetemcomitans. Nucleic Acids Res18:5291.
31.
GuthmillerJMKraigECagleMPKolodrubetzD (1990b). Sequence of the lktD gene from Actinobacillus actinomycetemcomitans. Nucleic Acids Res18:5292.
32.
GuthmillerJMKolodrubetzDKraigE (1995). Mutational analysis of the putative leukotoxin transport genes in Actinobacillus actinomycetemcomitans. Microb Pathog18:307-321.
33.
HaraszthyVIHariharanGTinocoEMCortelliJRLallyETDavisE. (2000). Evidence for the role of highly leukotoxic Actinobacillus actinomycetemcomitans in the pathogenesis of localized juvenile and other forms of early-onset periodontitis. J Periodontol71:912-922.
34.
HaubekDDirienzoJMTinocoEMWestergaardJLopezNJChungCP. (1997). Racial tropism of a highly toxic clone of Actinobacillus actinomycetemcomitans associated with juvenile periodontitis. J Clin Microbiol35:3037-3042.
35.
HaubekDEnnibiOKPoulsenKPoulsenSBenzartiNKilianM (2001). Early-onset periodontitis in Morocco is associated with the highly leukotoxic clone of Actinobacillus actinomycetemcomitans. J Dent Res80:1580-1583.
36.
HaubekDEnnibiOKPoulsenKVaethMPoulsenSKilianM (2008). Risk of aggressive periodontitis in adolescent carriers of the JP2 clone of Aggregatibacter (Actinobacillus) actinomycetemcomitans in Morocco: a prospective longitudinal cohort study. Lancet371:237-242.
37.
HayashidaHPoulsenKKilianM (2002). Differences in iron acquisition from human haemoglobin among strains of Actinobacillus actinomycetemcomitans. Microbiology148(Pt 12):3993-4001.
38.
HeTNishiharaTDemuthDRIshikawaI (1999). A novel insertion sequence increases the expression of leukotoxicity in Actinobacillus actinomycetemcomitans clinical isolates. J Periodontol70:1261-1268.
39.
HoggNSmithAMcDowallAGilesKStanleyPLaschingerM. (2004). How T cells use LFA-1 to attach and migrate. Immunol Lett92:51-54.
40.
HollandIBSchmittLYoungJ (2005). Type 1 protein secretion in bacteria, the ABC-transporter dependent pathway (review). Mol Membr Biol22:29-39.
41.
HorstERadaszkiewiczTHooftman-den OtterAPietersRvan DongenJJMeijerCJ. (1991). Expression of the leucocyte integrin LFA-1 (CD11a/CD18) and its ligand ICAM-1 (CD54) in lymphoid malignancies is related to lineage derivation and stage of differentiation but not to tumor grade. Leukemia5:848-853.
42.
HritzMFisherEDemuthDR (1996). Differential regulation of the leukotoxin operon in highly leukotoxic and minimally leukotoxic strains of Actinobacillus actinomycetemcomitans. Infect Immun64:2724-2729.
43.
InghiramiGWieczorekRZhuBYSilberRDalla-FaveraRKnowlesDM (1988). Differential expression of LFA-1 molecules in non-Hodgkin’s lymphoma and lymphoid leukemia. Blood72:1431-1434.
44.
InoueTTanimotoITadaTOhashiTFukuiKOhtaH (2001). Fermentable-sugar-level-dependent regulation of leukotoxin synthesis in a variably toxic strain of Actinobacillus actinomycetemcomitans. Microbiology147(Pt 10):2749-2756.
45.
InoueTFukuiKOhtaH (2006). Leukotoxin production by Actinobacillus actinomycetemcomitans. Toxin Reviews25:1-18.
46.
IsazaMPDuncanMSKaplanJBKachlanySC (2008). Screen for leukotoxin mutants in Aggregatibacter actinomycetemcomitans: genes of the phosphotransferase system are required for leukotoxin biosynthesis. Infect Immun76:3561-3568.
47.
IzanoEAWangHRagunathCRamasubbuNKaplanJB (2007). Detachment and killing of Aggregatibacter actinomycetemcomitans biofilms by dispersin B and SDS. J Dent Res86:618-622.
JohanssonAClaessonRHanstromLKalfasS (2003). Serum-mediated release of leukotoxin from the cell surface of the periodontal pathogen Actinobacillus actinomycetemcomitans. Eur J Oral Sci111:209-215.
50.
KachlanySCFineDHFigurskiDH (2000). Secretion of RTX leukotoxin by Actinobacillus actinomycetemcomitans. Infect Immun68:6094-6100.
51.
KachlanySCSchwartzABBalashovaNVHioeCETuenMLeA. (2009). Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells. Leukemia Res [Epub ahead of print]September9, 2009 (in press).
52.
KaplanJB (2009). Therapeutic potential of biofilm-dispersing enzymes. Int J Artif Org32:545-554.
53.
KaplanJBSchreinerHCFurgangDFineDH (2002). Population structure and genetic diversity of Actinobacillus actinomycetemcomitans strains isolated from localized juvenile periodontitis patients. J Clin Microbiol40:1181-1187.
54.
KatoSKowashiYDemuthDR (2002). Outer membrane-like vesicles secreted by Actinobacillus actinomycetemcomitans are enriched in leukotoxin. Microb Pathog32:1-13.
55.
KelkPJohanssonAClaessonRHanstromLKalfasS (2003). Caspase 1 involvement in human monocyte lysis induced by Actinobacillus actinomycetemcomitans leukotoxin. Infect Immun71:4448-4455.
KiebaIRFongKPTangHYHoffmanKESpeicherDWKlicksteinLB. (2007). Aggregatibacter actinomycetemcomitans leukotoxin requires beta-sheets 1 and 2 of the human CD11a beta-propeller for cytotoxicity. Cell Microbiol9:2689-2699.
KolodrubetzDDaileyTEbersoleJKraigE (1989). Cloning and expression of the leukotoxin gene from Actinobacillus actinomycetemcomitans. Infect Immun57:1465-1469.
60.
KolodrubetzDPhillipsLJacobsCBurgumAKraigE (2003). Anaerobic regulation of Actinobacillus actinomycetemcomitans leukotoxin transcription is ArcA/FnrA-independent and requires a novel promoter element. Res Microbiol154:645-653.
KorostoffJYamaguchiNMillerMKiebaILallyET (2000). Perturbation of mitochondrial structure and function plays a central role in Actinobacillus actinomycetemcomitans leukotoxin-induced apoptosis. Microb Pathog29:267-278.
63.
KraigEDaileyTKolodrubetzD (1990). Nucleotide sequence of the leukotoxin gene from Actinobacillus actinomycetemcomitans: homology to the alpha-hemolysin/leukotoxin gene family. Infect Immun58:920-929.
LallaELamsterIBHofmannMABucciarelliLJerudAPTuckerS. (2003). Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol23:1405-1411.
66.
LallyETGolubEEKiebaIRTaichmanNSRosenbloomJRosenbloomJC. (1989a). Analysis of the Actinobacillus actinomycetemcomitans leukotoxin gene. Delineation of unique features and comparison to homologous toxins. J Biol Chem264:15451-15456.
67.
LallyETKiebaIRDemuthDRRosenbloomJGolubEETaichmanNS. (1989b). Identification and expression of the Actinobacillus actinomycetemcomitans leukotoxin gene. Biochem Biophys Res Commun159:256-262.
68.
LallyETGolubEEKiebaIRTaichmanNSDeckerSBertholdP. (1991). Structure and function of the B and D genes of the Actinobacillus actinomycetemcomitans leukotoxin complex. Microb Pathog11:111-121.
69.
LallyETGolubEEKiebaIR (1994). Identification and immunological characterization of the domain of Actinobacillus actinomycetemcomitans leukotoxin that determines its specificity for human target cells. J Biol Chem269:31289-31295.
70.
LallyETKiebaIRSatoAGreenCLRosenbloomJKorostoffJ. (1997). RTX toxins recognize a beta2 integrin on the surface of human target cells. J Biol Chem272:30463-30469.
71.
LallyETHillRBKiebaIRKorostoffJ (1999). The interaction between RTX toxins and target cells. Trends Microbiol7:356-361.
72.
LamellCWGriffenALMcClellanDLLeysEJ (2000). Acquisition and colonization stability of Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in children. J Clin Microbiol38:1196-1199.
73.
LeeSFAndrianERowlandEMarquezIC (2009). Immune response and alveolar bone resorption in a mouse model of Treponema denticola infection. Infect Immun77:694-698.
74.
LeysEJGriffenALStrongSJFuerstPA (1994). Detection and strain identification of Actinobacillus actinomycetemcomitans by nested PCR. J Clin Microbiol32:1288-1294.
75.
LöeHBrownLJ (1991). Early onset periodontitis in the United States of America. J Periodontol62:608-616.
76.
MacheleidtAMullerHPEgerTPutzkerMFuhrmannAZollerL (1999). Absence of an especially toxic clone among isolates of Actinobacillus actinomycetemcomitans recovered from army recruits. Clin Oral Investig3:161-167.
77.
ManganDFTaichmanNSLallyETWahlSM (1991). Lethal effects of Actinobacillus actinomycetemcomitans leukotoxin on human T lymphocytes. Infect Immun59:3267-3272.
78.
MitchellCGaoLDemuthDR (2003). Positive and negative cis-acting regulatory sequences control expression of leukotoxin in Actinobacillus actinomycetemcomitans 652. Infect Immun71:5640-5649.
NagataHIkawaYKuboniwaMMaedaKShizukuishiS (2002). Characterization of hemoglobin binding to Actinobacillus actinomycetemcomitans. Anaerobe8:109-114.
81.
NewmanMGSocranskySSSavittEDPropasDACrawfordA (1976). Studies of the microbiology of periodontosis. J Periodontol47:373-379.
82.
NiedermanRKeldermanHSocranskySOstroffGGencoCKentRJr. (2002). Enhanced neutrophil emigration and Porphyromonas gingivalis reduction following PGG-glucan treatment of mice. Arch Oral Biol47:613-618.
83.
NishinoKYamadaJHirakawaHHirataTYamaguchiA (2003). Roles of TolC-dependent multidrug transporters of Escherichia coli in resistance to beta-lactams. Antimicrob Agents Chemother47:3030-3033.
84.
NishinoKLatifiTGroismanEA (2006). Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol Microbiol59:126-141.
85.
OhtaHKatoKKokeguchiSHaraHFukuiKMurayamaY (1991). Nuclease-sensitive binding of an Actinobacillus actinomycetemcomitans leukotoxin to the bacterial cell surface. Infect Immun59:4599-4605.
86.
OhtaHMiyagiAKatoKFukuiK (1996). The relationships between leukotoxin production, growth rate and the bicarbonate concentration in a toxin-production-variable strain of Actinobacillus actinomycetemcomitans. Microbiology142(Pt 4):963-970.
87.
OlsenEDuvicMFrankelAKimYMartinAVonderheidE. (2001). Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol19:376-388.
88.
PacelloFLangfordPRKrollJSIndianiCSmulevichGDesideriA. (2001). A novel heme protein, the Cu, Zn-superoxide dismutase from Haemophilus ducreyi. J Biol Chem276:30326-30334.
89.
PermpanichPKowolikMJGalliDM (2006). Resistance of fluorescent-labelled Actinobacillus actinomycetemcomitans strains to phagocytosis and killing by human neutrophils. Cell Microbiol8:72-84.
90.
PolakDWilenskyAShapiraLHalabiAGoldsteinDWeissEI. (2009). Mouse model of experimental periodontitis induced by Porphyromonas gingivalis/Fusobacterium nucleatum infection: bone loss and host response. J Clin Periodontol36:406-410.
91.
RhodesERTomarasAPMcGillivaryGConnerlyPLActisLA (2005). Genetic and functional analyses of the Actinobacillus actinomycetemcomitans AfeABCD siderophore-independent iron acquisition system. Infect Immun73:3758-3763.
92.
Sanchez-MagranerLVigueraARGarcia-PaciosMGarcillanMPArrondoJLde la CruzF. (2007). The calcium-binding C-terminal domain of Escherichia coli alpha-hemolysin is a major determinant in the surface-active properties of the protein. J Biol Chem282:11827-11835.
93.
SchaefferLMSchmidtMLDemuthDR (2008). Induction of Aggregatibacter actinomycetemcomitans leukotoxin expression by IS1301 and orfA. Microbiology154(Pt 2):528-538.
94.
SchlorSSchmidtAMaierEBenzRGoebelWGentschevI (1997). In vivo and in vitro studies on interactions between the components of the hemolysin (HlyA) secretion machinery of Escherichia coli. Mol Gen Genet256:306-319.
95.
SchreinerHCSinatraKKaplanJBFurgangDKachlanySCPlanetPJ. (2003). Tight-adherence genes of Actinobacillus actinomycetemcomitans are required for virulence in a rat model. Proc Natl Acad Sci USA100:7295-7300.
96.
ShenkerBJMcKayTDatarSMillerMChowhanRDemuthD (1999). Actinobacillus actinomycetemcomitans immunosuppressive protein is a member of the family of cytolethal distending toxins capable of causing a G2 arrest in human T cells. J Immunol162:4773-4780.
97.
ShenkerBJBesackDMcKayTPankoskiLZekavatADemuthDR (2005). Induction of cell cycle arrest in lymphocytes by Actinobacillus actinomycetemcomitans cytolethal distending toxin requires three sub-units for maximum activity. J Immunol174:2228-2234.
98.
SimpsonDLBertholdPTaichmanNS (1988). Killing of human myelomonocytic leukemia and lymphocytic cell lines by Actinobacillus actinomycetemcomitans leukotoxin. Infect Immun56:1162-1166.
99.
SlotsJ (2003). Update on general health risk of periodontal disease. Int Dent J53(Suppl 3):200-207.
100.
SlotsJTingM (1999). Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in human periodontal disease: occurrence and treatment. Periodontol 200020:82-121.
101.
SpitznagelJJrKraigEKolodrubetzD (1991). Regulation of leukotoxin in leukotoxic and nonleukotoxic strains of Actinobacillus actinomycetemcomitans. Infect Immun59:1394-1401.
102.
StanleyPPackmanLCKoronakisVHughesC (1994). Fatty acylation of two internal lysine residues required for the toxic activity of Escherichia coli hemolysin. Science266:1992-1996.
103.
StanleyPKoronakisVHughesC (1998). Acylation of Escherichia coli hemolysin: a unique protein lipidation mechanism underlying toxin function. Microbiol Mol Biol Rev62:309-333.
104.
TaichmanNSDeanRTSandersonCJ (1980). Biochemical and morphological characterization of the killing of human monocytes by a leukotoxin derived from Actinobacillus actinomycetemcomitans. Infect Immun28:258-268.
105.
TaichmanNSSimpsonDLSakuradaSCranfieldMDiRienzoJSlotsJ (1987). Comparative studies on the biology of Actinobacillus actinomycetemcomitans leukotoxin in primates. Oral Microbiol Immunol2:97-104.
106.
TamuraNMurakamiSOyamaYIshiguroMYamaguchiA (2005). Direct interaction of multidrug efflux transporter AcrB and outer membrane channel TolC detected via site-directed disulfide cross-linking. Biochemistry44:11115-11121.
107.
TsaiCCMcArthurWPBaehniPCHammondBFTaichmanNS (1979). Extraction and partial characterization of a leukotoxin from a plaque-derived Gram-negative microorganism. Infect Immun25:427-439.
108.
TsaiCCShenkerBJDiRienzoJMMalamudDTaichmanNS (1984). Extraction and isolation of a leukotoxin from Actinobacillus actinomycetemcomitans with polymyxin B. Infect Immun43:700-705.
109.
van WinkelhoffAJSlotsJ (1999). Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in nonoral infections. Periodontol 200020:122-135.
110.
WandersmanCDelepelaireP (1990). TolC, an Escherichia coli outer membrane protein required for hemolysin secretion. Proc Natl Acad Sci USA87:4776-4780.
111.
WinstonJLChenCKNeidersMEDyerDW (1993). Membrane protein expression by Actinobacillus actinomycetemcomitans in response to iron availability. J Dent Res72:1366-1373.
112.
YamaguchiNKiebaIRKorostoffJHowardPSShenkerBJLallyET (2001). Maintenance of oxidative phosphorylation protects cells from Actinobacillus actinomycetemcomitans leukotoxin-induced apoptosis. Cell Microbiol3:811-823.
113.
ZambonJJ (1985). Actinobacillus actinomycetemcomitans in human periodontal disease. J Clin Periodontol12:1-20.
