The role of oral bacteria in the pathogenesis of infective endocarditis K. W. Knox* N. Huntert

Key words: infective endocarditis, pathogenic mechanisms, oral bacteria. Abstract Various micro-organisms have been implicated as causative agents for bacterial endocarditis, including lactobacilli and in particular the viridans streptococci which are more commonly associated with dental caries. Of these, the most frequently isolated one has the descriptive name Streptococcus sanguis. The disease is characterized by growth of microorganisms within a platelet-fibrin thrombus protruding from a valve leaflet. An understanding of the pathogenesis involves knowledge of the mechanisms of conversion of the normal vascular surface to a thrombogenic one and the adhesion of micro-organisms to such surfaces. Model systems to study this interaction include experimental animals, mammalian epithelial cells and platelets, and proteins such as fibronectin and fibrinogen. Microbial protein surface components (adhesins) and lipoteichoic acid have also been implicated. Capsular polysaccharides may be involved, but the role of dextrans formed from sucrose has been overemphasized as the polymers are not formed in situ. Antibiotic prophylaxis for patients at risk is based on bacteriostatic or bactericidal action. However, bacterial cell surface components involved in adhesion may also be affected, and knowledge of such reactions could provide a more rational basis for antibiotic prophylaxis. (Received for publication February 1990. Revised September 1990. Accepted November 1990.)

*Director, Institute of Dental Research, Sydney. -)Principal Research Officer, Institute of Dental Research, Sydney. 286

Introduction Infective endocarditis, previously called subacute bacterial endocarditis, is one of the most serious complications of cardiac disease which may arise from dental treatment, and constitutes a significant and life-threatening medical and surgical problem.' T h e primary method of prevention is the provision of antibiotic prophylaxis to patients at risk, particularly those with rheumatic heart disease, valvular prostheses or with a history of infective endocarditis, and attention is generally directed towards the most appropriate procedure(s) for achieving this Knowledge of the aetiology of the disease would be expected to improve procedures for treatment, and such knowledge is now accumulating as a result of improvements in the identification of micro-organisms coupled with detailed studies on the microbial components associated with virulence, and on host responses. A pertinent point is that sub-bactericidal concentrations of vancomycin or amoxicillin may still prevent Streptococcus sanguis from causing endocarditis in experimental animals, because of a reduction in the ability of the organism to adhere to the damaged valve^.^ Streptococcus sanguis has a particular status in the history of the study of endocarditis as it was first isolated in 1946 from the .~ then a blood of a patient with e n d ~ c a r d i t i sSince wide range of micro-organisms has been implicated and the fact that these include fungi (for example, Candida) and rickettsiae is the reason for the deletion of the prefix 'bacterial' when identifying the disease. T h e source of the infecting organism can frequently be imputed. Thus, 50 per cent of patients with enterococcal endocarditis had undergone a gastrointestinal or urinary tract procedure, while 35 per cent of those with staphylococcal endocarditis showed a history of a staphylococcal lesion.' T h e extent to which dental procedures are Australian Dental Journal 1991;36(4):286-92.

a cause of endocarditis is difficult to quantitate, but it has been estimated that between 15 per cent' and 40 per cent3 of cases could be the result of dental treatment during the previous three months. The purpose of this paper is to identify the principal features of infective endocarditis and to highlight the important role that oral microorganisms may Play. Pathogenic mechanisms Predisposing factors Highly pathogenic organisms such as Streptococcus pyogenes and Staphylococcus aureus are able to colonize normal heart valves and produce disease in the uncompromised host. However, for a whole range of organisms of low to moderate pathogenicity, such as the oral streptococci, the evidence of both human and animal studies points to the requirement of a pre-existing abnormality within the vasculature or a compromised host defence system. Abnormalities affecting the endocardium include congenital defects, vegetations on the valves arising as a result of rheumatic fever, trauma arising from endoscopic procedures and alterations consequent upon placement of prosthetic valves. The group encompassing the compromised host includes drug addicts with intravenous habits, and frank immune deficiency such as the Acquired Immune Deficiency Syndrome (AIDS). T h e microbial aetiology is often unusual in this group but the oral cavity can frequently be imputed as a potential source of the organisms. The nature of the vascular surface T h e disease process of infective endocarditis is characterized by micro-organisms growing within a platelet-fibrin thrombus that protrudes from the valve leaflet. Fragments can break from this friable mass and be carried to distant sites resulting in multi-focal abscess formation. Two mechanisms have been proposed to account for the normally non-thrombogenic vascular surface being converted to a thrombogenic surface and the relative failure to contain the growth of the thrombi. In the first there could be microfocal denudation of endothelial cells overlying irregular fibrous tissue and exposed to extremely turbulent blood flow. This will trigger the intrinsic coagulation pathway. Current understanding of the key molecular events in this cascade reaction has been reviewed recently: and there are aspects which are particularly relevant to the present discussion. T h e plasma glycoprotein, von Willebrand factor, will adhere to an unknown basement membrane component, resulting in structural changes that expose Australian Dental Journal 1991;36:4

additional binding sites. One of these binds to the platelet membrane receptor complex, GP 1b-IX, thereby anchoring the platelet to the vessel wall; another binds to the platelet receptor, GPIIb-IIIa, leading to platelet aggregation and subsequent activation. The latter reaction depends on the recognition by GPIIb-IIIa of a tripeptide sequence in von Willebrand Factor, which is also found in other adhesive glycoproteins such as fibrinogen and fibronectin. T h e coagulation process is completed with the conversion of prothrombin to active thrombin which catalyses the formation of fibrin strands from fibrinogen and finally the cross-linking of the fibrin strands by Factor XIII. T h e second mechanism for thrombus formation involves the participation of the endothelial cells. It has been demonstrated that these cells can respond to the products of activated leukocytes, especially cytokines. These hormone-like polypeptides include interleukin-1, tumour necrosis factor, interleukin-6 and gamma interferon. Acting singly or in combination, the cytokines exert powerful effects on multiple systems including the vascular endothelium. Gamma interferon and tumour necrosis factor induce the expression of Class I1 major histocompatibility proteins at the endothelial cell surface. There is evidence that through these Class I1 proteins, endothelial cells are very effective in presenting antigen to helperhnducer T lymphocytes as a first step in activating the immune response.' While leukocyte margination and exchange occurs preferentially in post-capillary venules, especially where there are functionally adapted high endothelial cells,8 endothelial cells from various locations in the vascular bed can be induced by the action of cytokines to express leukocyte adhesion m o l e c ~ l e s .It~ is also pertinent that high concentrations of tumour necrosis factor can initiate vascular damage, possibly by promoting the binding of polymorphonuclear leukocytes to t h e endothelium, and activating the leukocytes to release granule contents and oxygen radical species with consequent damage to the endothelial cells.'O In addition to responding to cytokines released from leukocytes, endothelial cells could be a rich source of interleukin-1, which promotes inflammation.' This cytokine functions as a co-stimulant in lymphocyte activation and co-inducer of the acutephase protein response, as well as displaying mitogenic activity for fibroblasts and chemotactic activity for polymorphonuclear leukocytes. ' I While the levels of a number of plasma proteins rise in this response, increased levels of fibrinogen, a protein that contributes substantially to the 207

viscosity of blood and which is a major contributor to the matrix of the thrombus, could have a particular bearing on the progress of infective endocarditis. It is apparent then, that the endothelium has the potential to contribute indirectly to thrombus formation.

Oral micro-organisms implicated in endocarditis Streptococci Streptococci are the most common cause of endocarditis, with viridans streptococci accounting for approximately half of all cases. T h e term ‘viridans streptococci’ is applied to those organisms that are a-haemolytic or non-haemolytic on blood agar, generally susceptible to penicillin and commonly lacking a group antigen. While the connotation Streptococcus viridans is sometimes used, this is incorrect as a species has a much more defined range of properties. Defining the range of properties to be shared by a species has also led to extensive re-examination of the species of oral streptococci where the long-standing names are S. sanguis, S. mutans, S. milleri, S. salivarius, S. mitis, and S. mitior. As all of these species have been isolated from patients with endocarditis,”-” it is pertinent to refer to some aspects of nomenclature so that a meaningful assessment can be made of published papers. In the case of S. mutans the original species has been divided into several species, collectively known as mutans streptococci, which differ in a number of respects including their typing antigens and protein components;’* the two species most common in plaque are S. mutans, in its new restricted meaning, followed by S. sobrinus. The situation with S. milleri has been confused by differences in nonemclature so that three other aspects - S. constellatus, S. intermedius and S, anginosus - have been collectively referred to as the ‘S. milleri group’.1sSimilarly, it is appropriate to refer to the S. sanguis group to cover strains sometimes shown with the suffixes I and 11, the closely associated strains of S. mitis, S. mitior and S. oralis and those renamed as S. gordonii and S. parasanpis. Strains within the S. sanguis group account for 50 per cent of all viridans streptococci isolated from patients with endocarditis’”.13(and thus represent a quarter of all cases due to streptococci). Of the remaining 50 per cent of cases, at least half are associated with mutans streptococci and strains in the S. milleri group. Mutans streptococci 288

account for between 12 and 18 per cent of the viridans strains isolated in a number of s t ~ d i e s . ’ ~ , ’ ~ It also appears that they are primarily a pathogen in elderly patients with heart disease,” although their involvement may be more widespread as it is reported (by a New York group) that many clinical laboratories do not speciate the viridans streptococci.” Even where speciation has been performed and the name S. mutans has been used, it is now necessary to redefine strains under the new nomenclature. T h e role of strains from the S. milleri group in endocarditis and other infections is receiving increasing attention, and was the subject of two major reviews in 1988.’’.16 These strains account for 9-15 per cent of isolates of viridans streptococci from endocarditis patients, with a median value of 10 per cent for the seven survey^.'^ However, they are involved to a greater extent with suppurative lesions in almost every organ system, acute maxillary sinusitis and infection of implant material, and this suggests that they are better able to survive and grow in inflamed or necrotic tissue than many of the other streptococci.ls~’6 Emphasis on the cariogenic potential of the oral streptococci has tended to overshadow consideration of their other characteristics. Thus, it is an over-simplification to consider that S. sanguis and the S. milleri group are ‘safe’ just because they are assessed to be much less cariogenic than the mutans streptococci, when they can cause diseases much more serious than dental caries.

Lactobacilli Lactobacilli also have been generally considered in the context of dental caries, which has led to considerable interest in their classification by physiological and serological procedures.” However, several species, particularly Lactobacillus casei, have been isolated from patients with endocarditis.zO2 1 While the number of cases is small - 24 in a recent survey2’ - it should be borne in mind that they generally grow very poorly if at all on blood agar or nutrient agar so that their presence in clinical For this specimens may frequently be missed.*0~2’ reason they have been implicated as a possible cause of ‘culture-negative’ endocarditis, which accounts for 5-27 per cent of all cases.’ Other organisms Reports on the isolation of other organisms from patients with endocarditis appear regularly. Two of particular interest involve Actinobacillus actin~mycetemc~mitans,~~~~~ the Gram-negative organism most commonly associated with juvenile Australian Dental Journal 1991:36:4

periodontitis. In view of other reports where dental treatments have been recorded for periods up to three months prior to the appearance of symptoms, it may be significant that in one casez2there had been major dental treatment five months previously. However, another, more recent cause of bacteraemia cannot be ruled out and while the patient in this case 'did not have periodontitis', the authors recommend that the periodontal status of relevant patients be checked.22 Next to the streptococci the organisms most frequently associated with endocarditis are the staphylococci, particulary S. uureus,' which is also associated with a wide range of infections, including infected root canals, facial cellulitis, osteomyelitis of the jaw and dento-alveolar abscesses. The frequency of S. uu~eusassociation with endocarditis doubles for patients who are drug addicts to 40-60 per cent, primarily at the expense of streptococcal infections where the frequency drops to 14 per cent. I Drug addicts also show an increase in the frequency of occurrence of fungi as the cause of endocarditis - 14 per cent compared with 4 per cent in non-addicts.' Candidu ulbicuns and Cundidu parapsihis are prominent as causative organisms, providing another example of the increasing importance of C. ulbicuns in infections. It has also been noted that whereas the falling incidence of rheumatic fever should lead to fewer cases of endocarditis, the incidence could increase because of the increased susceptibility of drug addicts and also the more frequent insertion of prosthetic grafts and pacemakers.'

Pathogenic determinants of oral bacteria The bacterial cell surface For circulating bacteria to induce endocarditis, the first requirement is that they colonize the thrombotic vegetation comprising deposited platelets and fibrin. A large body of information has accumulated in recent years on the factors influencing microbial colonization of surfaces, and oral microbiologists have made major contributions to this Adhesion depends initially on non-specific factors, which are important in bringing the bacterial and mammalian cell surfaces into close juxtaposition when specific factors can come into operation. The non-specific factors are the negative charge on the bacterial cell surface and hydrophobicity, where a lessened water shell means the surfaces can come nearer together. Proteins display both properties, and strains that have lost the ability Australian Dental Journal 1991:36:4

to retain surface proteins show a concomitant decrease in hydrophobicity.26 Another important surface component produced by streptococci and lactobacilli is lipoteichoic acid (LTA), which was first described in collaborative studies between the Institute of Dental Research and Professor A. J. Wicken, University of New South wale^.^'^^^ Lipoteichoic acid carries a negative charge from the phosphate units in the teichoic acid chain and is also hydrophobic because of its lipid moiety. It would therefore be expected to contribute to the initial non-specific stage of adhesion, but it has also been implicated as playing a specific role in the adhesion of group A streptococci to mammalian cells.29 Generally, though, specificity depends on one of the surfaces containing a protein, variously called a lectin or adhesin, that binds to a receptor on the other surface in a manner analogous to the antigenantibody reaction. The adhesin may be a component of the mammalian cell surface, with the corresponding receptor on the bacterial cell surface, but it is more usual for the adhesin to be a bacterial surface component, frequently in the form of appendages called fimbriae or fibrils. Such structures have been recently identified on the surface of S. sang~is.~" S. salivurius3' and strains from the S. milleri group.32 Capsular polysaccharides are produced by some lact~bacilli'~ and strains from a number of species of viridans streptococci, namely S. sanguis, S. rnitis and those in the S. milleri group.33 Examination of streptococci grown in vivo and in vitro showed a capsule or glycocalyx that stained with ruthenium red.33 This detects acidic polymers, with the reactive component being either an acidic sugar in a polysaccharide or the more widespread LTA. Quantitation of the relative amounts of extractable glycocalyx by a simple carbohydrate analysis has led to the conclusion that the amount of glycocalyx is directly related to the size of cardiac vegetation (in the rabbit) and resistance to the action of peni~illin.~~ It is important to note that such a capsular polysaccharide or glycocalyx is produced in the absence of sucrose, and therefore is readily distinguishable from the dextrans (or glucans) that are only formed from sucrose by oral streptococci. This esssential distinction, which was also pointed out some years is still overlooked in the literature where the fact that strains isolated from patients with endocarditis can form these polysaccharides in vitro has been taken as indicating a causal association with endocarditis. 1 . 2 9 , 3 5 Organisms colonizing the thrombus could not synthesize dextrans as the 289

sucrose substrate is not available, although those entering the bloodstream from plaque could have dextrans on their surface. The production of glucans from sucrose by some of the oral streptococci is an obvious effect of growth conditions on the properties displayed by an organism. However, there are many other examples of the way in which a change in growth conditions can influence bacterial surface properties. For instance, a change in the growth rate (generation time), p H of growth, or even a change from glucose to fructose can dramatically affect the production of LTA, capsular polysaccharide and a range of p r o t e i n ~ . ~ ~ , ~ ’ Adhesion of bacteria to mammalian cells There is evidence that the propensity of an organism to adhere to platelets and to promote their aggregation in vitro is related to its capacity to colonize a platelet-fibrin thrombus induced by placement of an intracardiac catheter in experimental animals.38Studies on S. sanguis strains provide evidence for the involvement of both LTA38 and specific adhesin protein^,^' with S. sanguis and collagen sharing a common immunodeterminant that triggers the aggregation of platelets in plasma.39 Of particular significance is the observation that the adhesion of S. sanguzs to fibrin-platelet clots is decreased by treatment with penicillinz9 or amoxi ~ i l l i n probably ,~ due to binding to teichoic the loss of surface LTA4,4’or effects on specific proteins. Thus an understanding of the effect of antibiotics on bacterial surface properties could have important ramifications with respect to choosing the most appropriate antibiotic for treatment of infective endocarditis. A second attribute of potential importance is the capacity of the organism to adhere directly to endothelial cells, either normal or functionally altered as a result of a pre-existing lesion. This is supported by the recent report that strains of S. rnillerz, S. rnitis and S. sanguis isolated from patients with endocarditis adhered more effectively to rat heart endothelial cells than other strains from the throats of healthy individ~als.~’ There is also recent evidence that this interaction can induce phenotypic changes in both mammalian and bacterial cells,43 which has important implications. Binding of mammalian proteins by bacteria It has long been presumed that the binding of fibronectin andor fibrinogen by bacterial cells could play an important role in end~carditis.’~ According to a recent re vie^,'^ group A streptococci are amongst the few bacteria (out of the 30 examples 290

listed) that consistently bind fibronectin, with mutans streptococci, S. sanguis and S. salivarius displaying variable binding depending on the strain, and S. rnitis being amongst the major group with low or infrequent binding. In a recent study at the Institute of Dental 30 strains from the S. milleri group were compared for their ability to bind fibronectin; those from abscesses bound more fibronectin than other isolates, indicating a potential association between fibronectin binding and pathogenicity. T h e mechanism of the reaction of fibronectin with bacteria has been studied in detail with S. pyogenes where there is good evidence for LTA playing a specific (as distinct from non-specific) and with S. aureus, where a specific surface protein is The ability to bind fibrinogen has not been examined as extensively as that for fibronectin, but, again, S. pyogenes and S. aureus have received the most attention.29The binding of fibrinogen is often considered in the context of phagocytosis, which is discussed in the following section. Anti-phagocytic action Many micro-organisms have mechanisms to avoid phagocytosis by leukocytes. These include the hyaluronic acid capsule of S. pyogenes and the capsular polysaccharide of S. pneurnoniae. Another strategy is the employment of surface proteins for direct or indirect defence against phagocytes. Among the streptococci anti-phagocytic proteins have been reported in serological groups A, B and D, with the M protein of the group A streptococci the best studied e ~ a m p l e . ~T’h e principal mode of action of M protein seems to be that of binding fibrinogen so that a coat of host protein shields the microorganism. M protein could also have a direct action on leukoyctes, for example it has been shown to modulate actin p o l y m e r i z a t i ~ n . ~A~ high molecular mass protein, PI, isolated from S. r n u t ~ z n shas ~ ~ many of the properties of M protein including the induction of tissue cro~s-reactivity,~~ fibrinogen binding” and anti-phagocytic action;” serologically related proteins have been demonstrated in a number of other species of oral Gram-positive bacteria.” Promotion of thrombus formation In addition to the binding and activation of platelets with the resulting activation of the clotting cascade, micro-organisms and their products could activate the procoagulant activity of blood monocytes. This involves a bypassing of plateletderived Factor IV.’* A direct link back from activated phagocytes is the release of platelet activating Australian Dental Journal 1991:36:4.

factor by neutrophil polymorphonuclear leukocytes and monocytes.

Perspective Infective endocarditis continues to be a concern to practising dentists as the overall incidence has not declined appreciably despite the prevention of rheumatic endocarditis in industrialized countries. Oral micro-organisms account for a significant proportion of cases and mortality remains high at approximately 30 per cent. Understanding the basis of the induction and progression of the disease poses a substantial challenge. T h e key to this understanding is the dissection of the role of particular microbial determinants at different stages of the disease. Here experimental models are essential, and the model of colonization by intravenously administered bacteria of thrombi produced on heart valves by intracardiac catheterization of experimental animals has received considerable attention in the evaluation of the efficacy of antibiotics. This work has had a surprising result in demonstrating that antibiotics can be quite effective in the absence of significant bacteriostatic or bactericidal action because of the loss of key determinants from the bacterial s ~ r f a c e .The ~ , ~potential ~ of the animal model is yet to be fully utilized in furthering the understanding of microbial pathog e n i ~ i t y . ’One ~ area of promise is the effect of immunization of the experimental animals with bacteria or their products. A point of caution in this regard, however, is the possible side effects of vaccines containing tissue cross-reactive components such as protein P1. Finally, it is worth noting that there is renewed interest in a possible microbial based inflammatory process in the pathology of another major vascular disease, atheros~lerosis,~~ and that a recent study found a positive correlation between oral sepsis and myocardial infarction.” Perhaps the old concept of focal infection will experience a r e ~ i v a l ! ’ ~ Acknowledgement The authors’ work is supported by a Program Grant from the National Health and Medical Research Council. References I . King K, Harkness JL. Infective endocarditis in the 1980s. Part 1. Aetiology and diagnosis. Med J Aust 1986; 144:536-40. 2. King K, Harkness JL. Infective endocarditis in the 1980s. Part 2. Treatment and management. Med J Aust 1986; 144:588-94. 3. Ehrmann EH. Infective endocarditis and the dentist. Aust Dent J 1986;31:351-60. Australian Dental Journal 1991.36 4

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27. Knox KW, Wicken AJ. Immunological propenies of teichoic acids. Bacteriol Rev 1973;37:215-57. 28. Wicken AJ, Knox KW. Lipoteichoic acids: a new class of bacterial antigen. Science 1975;187:1161-7. 29. Christensen GD, Simpson WA, Beachey EH. Adhesion of bacteria to animal tissues - complex mechanisms. In Fletcher M, Savage DC, eds. Bacterial adhesion. New York: Plenum Publ, 1985:279-305. 30. Handley PS, Carter PL, Wyatt JE, Heskerh LM. Surface structures (peritrichous fibrils and tufts of fibrils) found on Streptococcus sanguis strains may be related to their ability to coaggregate with other oral genera. Infect Immun 1985;47:217-27. 31. Handley PS, Harty DWS, Wyatt JE, Brown CR, Doran JP, Gibbs AC. A comparison of the adhesion, coaggregation and cell-surface hydrophobicity properties of fibrillar and fimbriate strains of Streptococcus salivarius. J Gen Microbiol 1987;133:3207-17. 32. Willcox MDP, Drucker DB, Surface structures coaggregation and adherence phenomenon of Streptococcus orulis and related species. Microbiol 1989;59:19-29. 33. Mills J, Pullam L, Dall L, Marzouk J, Wilson W, Costenon JW. Exopolysaccharide production by viridans streptococci in experimental endocarditis. Infect Immun 1984;43:359-67. 34. Dall L, Herndon B. Quantitative assay of glycocalyx produced by viridans group streptococci that cause endocarditis. J Clin Microbiol 1989;27:2039-41. 35. Ramirez-Ronda CH. Adherence of glucan-positive and glucan-negative streptococci strains to normal and damaged heart valves. J Clin Invest 1978;62:805-14. 36. Knox KW, Wicken AJ. Effect of growth conditions on the surface properties and surface components of oral bacteria. In: Dean ARC, Ellwood DC, Evans CGT, eds. Continuous Culture 8: Biotechnology medicine and the environment. Chichester: Ellis Horwood, 1984:72-87. 37. Knox KW, Wicken AJ. Environmentally induced changes in the surfaces of oral streptococci and lactobacilli. In: Mergenhagen SE, Rosan B, eds. Molecular basis of oral microbial adhesion. Washington: American Society for Microbiology, 1985;2 12-9. 38. Herzberg MC, Brintzenhofe KL, Clawson CC. Aggregation of human platelets and adhesion of Streptococcus sunguis. Infect Immun 1983;39: 1457-69. 39. Erickson PR, Herzberg MC. A collagen-like immunodeterminant on the surface of Streprococcur sunguis induces platelet aggregation. J Immunol 1987;138:1360-6. 40. Kusser W, Zimmer K, Fiedler F. Characteristics of the binding of aminoglycosides to teichoic acids. A potential model system for the interaction of aminoglycosides with polyanions. Eur J Biochem 1985;151:601-5. 41. Nealon TJ, Beachey EH, Courtney HS, Simpson WA. Release of fibronectin-lipoteichoicacid complexes from group A streptococci with penicillin. Infect Immun 1986;51:529-35. 42. Schollin J, Danielsson D. Bacterial adherence to endothelial cells from rat heart, with special regard to alpha-hemolytic streptococci. Acta Path Microbiol Immunol Scand 1988:96:428-32.

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43. Finlay BB, Heffron F, Falkow S. Epithelial cell surfaces induce Salmonella proteins required for bacterial adherence and invasion. Science 1989;243:940-3. 44. Willcox MDP, Knox KW. Surface associated properties of Streptococcus milleri group strains and their potential relationship to pathogenesis. J Med Microbiol (in press). 45. Stanislowski L, Courtney HS, Simpson WA, Harty DL, Beachey EH, Robert L, Ofek I. Hybridoma antibodies to the lipid-binding site(s) in the amino terminal region of fibronectin inhibit binding of streptococcal lipoteichoic acid. J Infect Dis 1987;156:344-9. 46. Froman G , Switalski LM, Speziale P, Hook M . Isolation and characterization of a fibronectin receptor for Staphylococcus uureus. J Biol Chem 1987;262:6564-7 1. 47. Fischetti VA, Jones KF, Hollingshead SK, Scott JR. Structure, function and genetics of streptococcal M protein. Rev Infect Dis 1988;S356-9. 48. Chalovich JM, Fischett VA. Crosslinking of actin filaments and inhibition of actomyosin subfragment-I-ATPase activity by streptococcal M6 protein. Arch Biochem Biophys 1986;245:37-43. 49. Forester H, Hunter N, Knox KW. Characteristics ofa high molecular weight extracellular protein of Srreprococcus mutuns. J Gen Microbiol 1983; 129:2779-88. 50. Knox KW, Elliott C, Ballesteros M, Hunter N. Biological properties of PI-related proteins from oral streptococci. In: Lutticken R, ed. Xth Lancefield Int Symp streptococci and streptococcal diseases. (in press). 51. Forester H, Hunter N, Lowden JA, Weston KM, Knox KW. Protein PI of Streprococcus murans: an M-protein-like virulence factor of oral streptococci. In: Kimura Y, Kotami s, Shiokawa Y, eds. Recent advances in streptococci and streptococcal diseases. Oxford: Reedbooks, 1985: 107-8. 52. Lyberg T, Prydz H. Phorbol esters induce synthesis of thromboplastin activity in human monocytes. Biochem J 1981; 194:699-706. 53. Baddour LM, Christensen GD, Lowrance JH, Simpson WA. Pathogenesis of experimental endocarditis. Rev Infect Dis 1989;11:452-63. 54. Virella G, Lopes-Virella MF. Infections and atherosclerosis. Transplant Proc 1987;19:26-35. 55. Mattila K, Nieminen MS, Valtonen VV, et al. Association between dental health and acute myocardial infarction. Br Med J 1989;298:779-81. 56. Hunter N. Focal infection in perspective. Oral Surg Oral Med Oral Path 1977;44:626-7.

Address for correspondenceheprints: Institute of Dental Research, United Dental Hospital of Sydney, 2 Chalmers Street, Surry Hills, New South Wales, 2010.

Australian Dental Journal 1991;36:4.

The role of oral bacteria in the pathogenesis of infective endocarditis.

Various micro-organisms have been implicated as causative agents for bacterial endocarditis, including lactobacilli and in particular the viridans str...
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