International Journal of Health Sciences and Research www.ijhsr.org ISSN: 2249-9571

Review Article

Aggregatibacter Actinomycetemcomitans, an Aggressive Oral - A Review

D Mythireyi1, MG Krishnababa2

1Dept of Periodontics, SRM Dental College, SRM University, Chennai, India 2Dept of Periodontics, Sathyabama Dental College, Chennai, India

Correspondence Email: [email protected]

Received: 10/07//2012 Revised: 31/07/2012 Accepted: 10/08/2012

ABSTRACT

Aggregatibacter actinomycetemcomitans, an oral commensal which is also an opportunist pathogen has a distinct racial bias and a surprising range of potential virulence factors and virulence mechanisms. It is a pathogen not only in the periodontium but also in some non oral infections, possesses several virulence determinants which contribute to its ability to colonize the oral cavity, persist in the periodontal pocket, resist and evade host defenses, cause destruction to soft and hard tooth-supporting tissues, and interfere with host tissue repair after infection. The purpose of this review is to elaborate the microbiological aspects of this bacteria which makes it clinically significant. Keywords: Aggregatibacter actinomycetemcomitans, aggressive periodontitis, leukotoxin

I INTRODUCTION increases. [3] In periodontitis , only 10 to 30 species, mainly gram negative More than 500 cultivable bacterial anaerobic bacteria, are putative pathogens. species have been isolated from the [4] Three species gingival crevices of human beings, [1] but actinomycetemcomitans , Porphyromonas the actual species count may be gingivalis and Bacteroides forsythus are thousands, since a wide proportion of presently considered as periodontal bacteria remains uncultivable or pathogens and primary etiological agents unidentified. [2] The sub gingival in periodontitis (World Workshop in bacterial flora consists of facultatively Periodontics 1996 ). Additional putative anaerobic gram positive species in the periodontal pathogens include Prevotella healthy oral cavity, but in gingivitis the intermedia, Prevotella nigrescens, proportion of gram negative bacteria Campylobacter rectus , Fusobacterium International Journal of Health Sciences & Research (www.ijhsr.org) 105 Vol.2; Issue: 5; August 2012 nucleatum , Peptostreptococcus micros and was first isolated from human spirochetes ( American Academy of cervicofacial actinomycosis together with Periodontology 1992 , Haffajee & Actinomyces and was thus described as Socransky 1994 , World Workshop in Bacterium actinomycetemcomitans by Periodontics 1996 ) Klinger in 1912. [9] Later Lieske in 1921 reclassified as Bacterium comitans. II HISTORICAL PERSPECTIVE During the past 95 years , the taxonomic A. actinomycetemcomitans was first position has met several changes . In isolated and identified in 1912 by Klinger. [5] 1929 , Topley and Wilson changed the It was so named because of its consistent genus name to Actinobacillus although association with Actinomyces israelii in Bacterium actinomycetemcomitans had a actinomycotic infections. In 1934 Klaber weak resemblance to Actinobacillus reported that this organism occurred only in lignirersiii , the type species of the genus association A. israelli. Heinrich and Pulverer Actinobacillus . In the name (1959) reported that 30% of actinomycotic Actinobacillus actinomycetemcomitans , lesions contained this organism. However the new genus name refers to the star King and Tatum in 1962 reported instances shaped structure ( Greek actis “ray “ ) in of infection with A.actinomycetemcomitans the centre of the colonies of rod shaped unconnected with diagnosed actinomycosis. cells. They considered this organism to be an King & Tatum (1962) [10] described important etiologic agent of endocarditis. [6] the close phenotypic similarity of Since that time more cases of Actinobacillus actinomycetemcomitans with A.actinomycetemcomitans endocarditis have H. aphrophilus, and Actinobacillus been reported (Mitchell & Gillespie 1964, actinomycetemcomitans was subsequently Goss et al 1967 , Affias et al 1978). It has reassigned to the genus as also been reported in brain abscess (Martin Haemophilus actinomycetemcomitans by et al 1967), urinary tract et al infection Potts et al 1985. [11] The genus change (Townsend & Glenwatter 1969), infection of was however, not favoured , as thyroid gland (Burgher et al 1973) Actinobacillus actinomycetemcomitans osteomyletis (Muhle et al 1979). A. was not closely related to Haemophilus actinomycetemcomitans was first influenza , the type species of the genus recognized as a possible periodontal Haemophilus. [12] The difference between pathogen by its increased frequency of Actinobacillus actinomycetemcomitans and detection and higher numbers in lesions of is based on a localized juvenile periodontitis (Newman et number of chemotaxonomic characteristics al 1976, Slots 1976, Newman & Socransky as well as on 16S rRNA gene sequence 1977, Slots et al 1980, Mandell & Socransky phylogeny . Therefore the previous genus 1981, Zambon et al 1983, Chung et al 1989 ) Actinobacillus was reinstated. [13] [7] Phylogenetic analysis of the three genera , Actinobacillus - III TAXONOMIC CLASSIFICATION Haemophilus – Pasteurella , based on Aggregatibacter (previously 16SrRNA gene sequences , revealed that Actinobacillus actinomycetemcomitans), a Actinobacillus actinomycetemcomitans is member of family Pasteurellaceae, [8] has closely related been recognized as one of the key and Haemophilus paraaphrophilus and pathogens in periodontitis. This bacterium that these three species together with International Journal of Health Sciences & Research (www.ijhsr.org) 106 Vol.2; Issue: 5; August 2012

Haemophilus segnis formed a single into well developed colonies takes phylogenetic cluster . Due to their 24-48hrs. On solid growth media, fresh phylogeny and their typical phenotypic A. actinomycetemcomitans isolates adhere charecteristics - the autoaggregation, the to agar and form circular colonies 0.5 to species Actinobacillus 1mm in diameter with slightly irregular actinomycetemcomitans, Haemophilus edges. aphrophilus , Haemophilus paraaphrophilus Fresh oral isolates of A. and were recently actinomycetemcomitans are invariably reclassified to a novel genus fimbriated and form small ( ~1mm ), Aggregatibacter by Norskov – Lauritsen rough surface, translucent colonies, with an and Kilan; 2006. [14] internal star shaped morphology. Repeated subculturing of the clinical isolates Taxonomic classification: Full lineage: results in a spontaneous change from Domain Bacteria rough to smooth colony morphology as Phylum represented by A. actinomycetemcomitans Class strains from American Type Culture Order Parteurellales [15] Family Pasteurellaceae Collection. Genus Aggregatibacter The rough colony morphology and Species actinomycetemcomitans the tight adherence (autoaggregation Taxonomic I D 714 phenotype ) have been attributed to the Type strain ATCC33384 presence of long and bundled fimbriae NCTC 9710 on the cell surface . Colonies of the

smooth variants lack the star like inner IV CULTURAL CHARECTERISTICS structure and the cells do not express A actinomycetemcomitans is a fimbriae. [16] The non fimbriated smooth small non motile Gram negative colony variants grow as large , round coccobacillus. It is capnophilic and opaque colonies on agar. facultatively anaerobic, it grows well in 5%

CO2 in air or anaerobically and growth

Figure 1 : Photograph of a primary isolation plate of a sub gingival plaque sample from a diseased site from a subject with LJP. The majority of small round convex colonies on this plate are isolates of A. actinomycetemcomitans

Occasionally the rough to smooth transition goes through an intermediate phase in which the colonies are translucent but smooth surfaced. Genes for the fimbriae biogenesis of A.

International Journal of Health Sciences & Research (www.ijhsr.org) 107 Vol.2; Issue: 5; August 2012 actinomycetemcomitans reside in the 12-kb flp operon that contains 14 genes flp-1-flp-2- tadV- rcpCAB-tadZABCDEFG. The transcription - initiation points of the operon were located at 101 and 102 nucleotides upstream of flp – 1

A B Figure-2. Colony morphology of an A. actinomycetemcomitans strain on A. specific medium, and B , a nonspecific medium The internal star is easily seen

V BIOCHEMICAL  Fresh clinical isolates are adherent to CHARECTERISTICS the agar , difficult to emulsify  Lack of growth on Mac Conkey and  Prolonged incubation (5 to 7) days – other enteric agars colonies may develop a central  Catalase production : + ve density that appears as four or six  Nitrate reduction : + ve pointed star. This characteristic is  Oxidase negative : + ve ( occasional lost on repeated subcultures and the strains may be weakly positive ) colonies become less adherent  Urease : - ve Growth in broth:  Indole production : - ve  Growth is scant and adherent to sides  X V factor requirement : - ve of the tube  Glucose , Fructose , Mannose : VI FACTORS INFLUENCING THE strong fermentation GROWTH AND VIABILITY OF A.  Acid production from maltose , ACTINOMYCETEMCOMITANS mannitol and xylose varies The addition of increasing concentrations of yeast extract to  Non – haemolytic bacteriological medium increased the Based on the variability in fermenting growth rate of several A. maltose, mannitol, xylose and dextrin A. actinomycetemcomitans strains.The actinomycetemcomitans strains have been addition of L- cysteine resulted in grouped into 10 biotypes bacterial growth rates comparable to those with yeast extract. Thiamine Growth on chocolate and blood agar: increased the growth of several A. actinomycetemcomitans strains but did not  Grows slowly result in growth rates comparable to  Visible colonies appear after 48 to 72 those with yeast extract. The addition of hrs physiological concentrations of steroid  Colonies are small, smooth , hormones to bacteriological medium translucent, non haemolytic and have enhanced the growth of A. slightly irregular edge International Journal of Health Sciences & Research (www.ijhsr.org) 108 Vol.2; Issue: 5; August 2012 actinomycetemcomitans. Additional iron adhesion determinants for initial compounds and fat soluble vitamins had attachment of A. no influence on A. actinomycetemcomitans to oral actinomycetemcomitans growth. The surface. optimal pH range for A.  Bacterial interactions: Bacterial actinomycetemcomitans was between pH interactions or interbacterial 7.0 – 8.0 in a medium containing 0.5 – 1 antagonism seem to be another % NaCl. Several interesting observations determinant of oral colonisation of on the viability of A. actinomycetemcomitans. A.actinomycetemcomitans were made . A Hillman and co – workers ( 1982, rapid reduction of 1985, 1987 ) showed that certain species A.actinomycetemcomitans a viability such as Streptococcus sanguis , occurred following suspension in distilled Actinomyces naeslundi genospecies 2 and water . The presence of detergent Triton Streptococcus uberis produced factors X – 100 at concentrations above 2% ( that were inhibitory to the growth of A. u/v) also decreased the viability of A. actinimycetemcomitans. The mechanism of actinomycetemcomitans within 10 min. [17] inhibition was shown to be hydrogen peroxide formation by the “ beneficial VII VIRULENCE FACTORS species “, which either directly or via a Virulence factors host peroxidase system inhibited the  Leukotoxin pathogen.  Endotoxin Stevens et al. ( 1987 ) and Hammond  Collagenase et al ( 1987 ) demonstrated the reverse  Bacteriocin antagonism. A. actinomycetemcomitans  Cytolethal distending toxin was shown to specifically inhibit the  Adhesins growth of S. sanguis, S. uberis, and A. naeslundii genospecies 2 ( but not other  Neutrophil inhibitor species ) by the production of a  Fc binding proteins bacteriocin. This mutual antagonism is A. actinomycetemcomitans is one of the highly specific and its outcome may few oral bacteria capable of colonizing strongly influence whether a subject or a buccal mucosa as well as dental plaque. site will exhibit disease due to A. The establishment of actinomycetemcomitans. A.actinomycetemcomitans in the human  Vesicles: Aa elaborates numerous oral cavity is dependent on appropriate vesicles or “ blebs” on the cell attachment sites for initial colonisation surfaces. Their role in initial and is influenced by the interacting colonisation, if any , remains to be microflora and various host factors determined .

 Plasmids and Bacteriophages: Aa colonisation factors; Plasmids and bacteriophages are

 Pili or fimbriae genetic elements that may alter  Capsule the physiological properties of a  Interactions with other bacteria microorganism , contribute to  Vesicles virulence , modify taxonomic status  Fimbriae (pili): They are thin , and spread biological properties surface appendages that serve as

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among different strains, species , actinomycetemcomitans which has been and genera. thought to be entirely cell associated ; About 5 percent of clinical isolates of either bound to cell surface – associated A. actinomycetemcomitans show small or nucleic acids or within membranous larger cryptic ( i.e., with unknown vesicles which bud from the bacterium‟s function ) plasmids . surface. This means that the bacterium itself is toxic to target cells. VIRULENCE FACTORS: A.actinomycetemcomitans leukotoxin It must be emphasized that , specifically kills leucocyte function although a large numbers of „virulence associated antigen bearing cells such as factors‟ of A. actinomycetemcomitans polymorphonuclear leucocytes and have been identified, there have been no macrophages, whereas other types of cells in- vivo studies with isogenic mutants to (e.g.: epithelial and endothelial cells, establish that any of these proteins are fibroblasts, erythrocytes and platelets) are implicated in tissue pathology. resistant to lysis. Leukotoxin: A actinomycetemcomitans The leukotoxin mediated killing is leukotoxin was found in the end of 1970‟s. extremely rapid ( a matter of minutes ) It is a 116kDa protein and a member of and is caused by formation of pores in the RTX ( repeats in toxin ) family whose the cell membrane of target cells.. Cell cellular receptor is the beta 2 – integrin , lysis might be induced by the rapid LFA-1, thus accounting for its selective formation of highly conducive ion effect on leukocytes ( although only channels that lead to membrane those from primates ) . depolarization , loss of intracellular K+ , The gene operon that produces A. osmotic swelling and subsequent cell actinomycetemcomitans leukotoxin is death .Some A. actinomycetemcomitans designated as lkt. The leukotoxin operon strains produce higher amounts of consists in transcription order , of four leukotoxin than the others. Best known genes – lktC, A, B and D . The lktA of the high producers are the JP2 – like protein is the active toxin and this has clones , first reported for the strain JP2 to be acylated, by lktC and an acyl that was recovered from an African – carrier protein, to be biologically active. American individual with localized The other two proteins (lktB and lktD ) juvenile periodontitis. Molecular analysis are responsible for transport and of lkt operon revealed that a 530- bp secretion of lktA . Interestingly , although deletion in the promoter region of the different strains of lktA genes is a possible reason for A.actinomycetemcomitans express enhanced leukotoxin production in these different levels of leukotoxin, they all strains. Except for the JP-2 like strains , have the genes for leukotoxin operon . also strains without the 530-bp deletion The differences in leukotoxin expression in the promoter region can produce appear to be due to transcriptional elevated amounts of leukotoxin A. regulation since there is a direct actinomycetemcomitans produces higher correlation between the level of amounts of leukotoxin in anaerobic leukotoxin and the amount of lkt RNA in conditions than in aerobic conditions a given strain. The RTX leukotoxins are which is due to the presence of a 35 – secreted , and the only exception to this bp oxygen response element that is the lkt toxin of A. International Journal of Health Sciences & Research (www.ijhsr.org) 110 Vol.2; Issue: 5; August 2012 represents leukotoxin production in studies suggest that these molecules may aerobic conditions. function to inhibit complement activation. Superantigens: Chemotactic inhibitor: Superantigens are generally Neutrophils are recruited to bacterial proteins that activate T cells infected areas by following a bearing specific V beta T- cell receptors. concentration gradient of chemotactic One consequence of such activation is signals. Disruption or inhibition of that the T cells apoptose and thus neutrophil chemotaxis is advantageous for superantigens can be considered as the infecting organism. A. immunosuppresants. actinomycetemcomitans has been shown Cytolethal distending toxin : to be capable of inhibiting chemotaxis. The cytolethal distending toxin ( Immunosuppressive factor: CDT ) is a cell cycle – modulatory A. actinomycetemcomitans has protein with immunosuppressive function . been shown to produce a protein capable This toxin is the product of a three gene of inhibiting DNA, RNA, and protein operon ( cdtA, cdtB, cdtC ) which is synthesis in human T cells activated by found in a range of bacteria including mitogens or antigens. The purified , Shigella spp., protein is capable of inhibiting IgG and Campylobacter spp., Helicobacter spp. IgM production by human B cells and affects immunoglobulin production by interfering with the early stage of cell activation. Although the exact mechanism by which immunosuppressive factor (ISF) acts to cause immunosuppression is not known, it appears that this factor affects both B lymphocytes and T- regulatory

Figure 5: Crystal structure of cytolethal distending cells. toxin Lipopolysaccharide: A. actinomycetemcomitans The mechanism of action of this lipopolysaccharide (LPS) has been toxin is believed to be due to nuclease extensively charecterised both structurally activity of cdtB . In some, as yet and functionally. unexplained manner, cdtA and cdtC are  LPS is toxic to human NK cells believed to facilitate the entry of cdtB  LPS induces the production of into host cells. The cdtB is believed to cytokines such as IL-6 , IL-8 , IL- enter into the nucleus and degrade 1B and TNFA from different host chromosomal DNA, thus inducing cell cells, thus promoting inflammatory cycle arrest in G2/M phase via specific reaction. checkpoint kinases .  It also induces bone resorption in Fc binding proteins: vitro and in vivo, which may The role of Fc receptors found on enhance progression of the bacterial surfaces and those released periodontitis in soluble form during growth is not  actinomycetemcomitans LPS may well established. However, in vitro also contribute to destruction of periodontal connective tissue by

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activating the pathways that lead cells at higher HSP to stimulation of matrix concentrations. metalloproteinases and plasminogen activator. As mentioned above, bacterial and  Recently, A. human HSPs share high sequence actinomycetemcomitans LPS has homology. Antibodies raised against shown to induce foam cell GroEl – like proteins from formation and cholesteryl ester A.actinomycetemcomitans , P. gingivalis accumulation in murine and B. forsythus show a high level of macrophages which suggests that cross reactivity to each other. [18, 19] it also has proatherogenic activity. Actinomycetemcomitin: A new Cytokine inducer proteins secreted by bacteriocin produced by A. bacterium: actinomycetemcomitans  Cell stress protein, chaperonin Lima FL et al 2008 isolated a 60 : bacteriocin named as . Potent bone degrading actinomycetemcomitin from molecule . This molecular A.actinomycetemcomitans P ( 7-20) strain chaperone, which is that is active against Peptostreptococcus normally intracellular, anaerobius ATCC 27337. appears to be secreted by Actinomycetemcomitin was produced this bacterium and during exponential and stationary growth stimulates bone resorption phases and its amount decreased until it by acting as an osteoclast “ disappeared during the decline growth growth factor” phase.  Heat shock proteins: . Several authors have VIII DIAGNOSTIC METHODS reported in A. Commercial diagnostic kits: actinomycetemcomitans the 1. Evalusite ( Kodak) This is a number presence of HSPs of enzyme linked immunosorbant including GroEL- like ( assays (ELISA ) using antibodies to HSP-60) and DnaK like ( detect antigens for HSP -70) proteins. Protein A.actinomycetemcomitans. The homologous to GroEL-like reactions are carried out in a simple HSP found in the surface chair side reaction kit. Subgingival associated material of A. plaque samples are reacted with the actinomycetemcomitans antibodies and detection substrate in has osteolytic activity by a multilevel reaction dish. murine bone resorption 2. Omnigene (Omni Gene, Inc ) and assay. Purified native BTD ( Biotechnica Diagnostics , GroEl – like HSP from Inc) These are DNA probe systems A.actinomycetemcomitans for a number of subgingival bacteria. promotes epithelial cell A paper point sample of subgingival proliferation at lower HSP plaque is placed in a container concentrations, but has a provided and mailed off to the toxic effect on epithelial company for assay.

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Selective medium for isolation of A.actinomycetemcomitans on AASM A.actinomycetemcomitans: medium was 94.4% [23] Socransky et al 1981 developed a Phenotypic typing methods selective medium , malachite green Biotyping: Serological typing: bacitracin agar , for the isolation of Upto now six A. actinomy- A.actinomycetemcomitans. the medium cetemcomitans serotypes have been consists of Trypticase soy agar 40 gm/l , designated (a through f). The serological bacitracin 128µg/ml , malachite green specificity is defined by six structurally and 8µg/ml and 5% defibrinated sheep blood. antigenically distinct O-polysaccharide The medium, when incubated in an components of their respective atmosphere of air plus 10% CO2 for 5 lipopolysaccharide molecules (Page et al., days, permitted greater than 80% 1991; Perry et al., 1996a, b; Kaplan et al., recovery of pure cultures of 2001). However 3% to 8% of A. A.actinomycetemcomitans when compared actinomycetemcomitans isolates remain with a non selective media. [20] non serotypeable. [24] Slots et al 1982 developed TSBV Most periodontal patients with A. ( tryptic soy- serum – bacitracin – actinomycetemcomitans infections harbor vancomycin ) agar. TSBV agar contained only one serotype. Multiple serotypes ( or ( per litre ) 40 g of tryptic soy agar , 1 g serotypeable and non serotypeable of yeast extract , 100 ml of horse serum isolates ) are found in less than 10% of , 75 mg of bacitracin and 5 mg of the subjects. The serotype distribution of vancomycin. The TSBV medium A. actinomycetemcomitans in oral cavities suppressed most oral species and of periodontal patients seems to be permitted significantly higher recovery of heterogenous: A.actinomycetemcomitans than non  serotype a in 25% selective blood agar medium. [21]  serotype b in 29 % Martijn van Steenbergen T J et al  serotype c in 23 to 26 % 1986 compared the two selective media  serotype d in 3 to 4 % Malachite green bacitracin agar ( MGB  serotype e in 6 to 10 % and agar ) and tryptic soy serum bacitracin  non serotypeable isolates in 3 to 5 vancomycin ( TSBV ) agar . The highest % of subjects. [25] recovery was found on TSBV agar plates cultured in air - 5% CO2 both for The only study on the A. plaque samples from periodontal pockets actinomycetemcomitans serotype and for pure cultures. [22] distribution in non oral infections Tsuzukibashi O et al 2008 suggested the predominance of serotype c developed a novel selective medium in 72 % of subjects. [26] The serotype designated as AASM . It was prepared specificity is located in the by adding 200µg/ml of vancomycin and lipopolysaccharide ( LPS ) O – antigen . 10µg/ml of bacitracin to AAGM , which The chemical structures of the LPS – O contains dextrose , sodium bicarbonate , antigen of A.actinomycetemcomitans have trypticase soy , yeast extract and agar. been resolved for all six serotypes. They showed that all serotypes ( a-f ) of While serotypes a, b, c, e and f contain A.actinomycetemcomitans strains grow repeated disaccharide or trisaccharide well and the average growth recovery of units in their O- antigens ; Serotype d has tetrasaccharide repeating units. [27] International Journal of Health Sciences & Research (www.ijhsr.org) 113 Vol.2; Issue: 5; August 2012

Phylogenetic analysis of A.  Amplified fragment length actinomycetemcomitans strains have polymorphism (AFLP) revealed genetic diversity among the These methods have been successfully used serotypes . Based on the 16SrRNA gene to type A.actinomycetemcomitans sequencing, arbitrarily primed polymerase chain reaction and PCR and / or IX PRO- ATHEROGENETIC restriction endonuclease analysis of PROPERTIES OF certain genes or gene clusters, three A.ACTINOMYCETEMCOMITANS distinct phylogenetic lineages of A. An association between actinomycetemcomitans serotypes have cardiovascular and periodontal disease been distinguished . Serotype b and c each may be due to lipopolysaccharide (LPS) form separate lineages and the third promoted release of inflammatory lineage consists of serotypes a, d, e and mediators, adverse alterations in f. [28] It has been suggested that the lipoprotein profile and an imbalance in genetic dissimilarities among A. cholesterol homeostasis. Laura Lakio et al actinomycetemcomitans serotypes may in 2006 studied the proatherogenic relate to variation in virulence potential properties of LPS preparations from and to the specific associations between serotypes b and d strains on certain serotypes or genotypes and macrophages ( RAW 264.7) . A. periodontitis. For eg: while serotype c is actinomycetemcomitans LPS preparations dominant in periodontally healthy induced a time dependant release of TNF individuals serotypes a and/ or b are most – α and IL-1β . LPS induced foam cell frequently found in periodontitis than in formation and cholesterol ester health and serotype b and c in non – oral accumulation from native low density infections . There seems to be , however, lipoprotein in following order A. geographic / racial / ethnic differences in actinomycetemcomitans strains JP2 ( the serotype distribution in periodontitis. serotype b ) > Y4 (serotype b ) > IDH781 Serotypes d, e and f are only rarely ( serotype d ) mRNA expression levels of isolated from any population. Association scavenger receptor class B , type I and have also been reported between ATP- binding cassette transporter -1 periodontitis and certain restriction receptors mediating cholesterol efflux fragment length polymorphisms ( RFLP ) from macrophages were decreased by genotypes and AP-PCR genotypes . LPS preparations. The result suggest that Phage typing: Different strains within a the pro -atherogenic potential of species have different sensitivities for the A.actinomycetemcomitans LPS may lytic activity of bacteriophage. Phage typing depend on the infecting strain and is not available for correlate with the periodontopathogenic A.actinomycetemcomitans. [20] potential of the pathogen. [29] Molecular typing methods:  Restriction enzyme analysis ( REA ) X A.ACTINOMYCETEMCOMITANS  Restriction fragment length AND AGGRESSIVE PERIODONTITIS polymorphism (RFLP) Localised Aggressive periodontitis  Ribotyping: Pulse field gel This species was first recognized electrophoresis (PFGE) as a possible periodontal pathogen by its  Arbitrarily primed (AP)-PCR increased frequency of detection and high numbers in lesions of localized juvenile International Journal of Health Sciences & Research (www.ijhsr.org) 114 Vol.2; Issue: 5; August 2012 periodontitis ( Newman et al. 1976, Slots REFERNCES 1976, Newman & Socransky 1977, Slots et al. 1980, Mandell & Socransky 1981, 1. 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