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Defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause infective endocarditis
Medical Hypotheses 73 (2009) 1055–1057
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause infective endocarditis Junjun Lu, Wenzhen Zhang, Yuqing Hao *, Yunwo Zhu State Key Laboratory of Oral Diseases, Sichuan University, No. 14, 3rd Section Renmin South Road, Chengdu, Sichuan 610041, China
a r t i c l e
i n f o
Article history: Received 5 May 2009 Accepted 10 May 2009
s u m m a r y Infective endocarditis (IE) is a rare but life-threatening infection. Bacteremia with organisms known to cause IE occurs commonly in association with invasive dental origin. Despite daily oral activities as well as professional dental treatments inducing bacteremia and the dental bacteremia as a risk factor of IE, the details of dental bacteria in the pathogenesis of IE are far from elucidation to date. How do a few microorganisms survive host defenses or escape from antibiotic attacking to seed target organs and cause distant infections? Why are Gram-positive bacteria more frequently detected than Gram-negative bacteria in IE? Cell wall-deficient bacteria (CWDB) were traditionally defined as bacteria with altered morphology and consistent with damaged or absent cell wall structures identified by EM. A number of case reports and laboratory studies suggest that CWDB may be found in the peripheral blood of patients with IE, and may also be demonstrated in vegetations on the valves of patients with IE. CWDB, in vitro, are resistant to antibiotics that act on cell wall biosynthesis. Recent studies indicate that the Streptococcus mutans (S. mutans) strains, the major cariogenic bacterium, isolated from the infected valve were deficient in some wall-associated proteins which are main cariogenic virulence of S. mutans, and the deficient stains exhibited less susceptible to antibiotics that act on cell wall biosynthesis. Further, the cloned deficient mutans were less susceptible to phagocytosis by human polymorphonuclear leukocytes but to possess higher platelet aggregation properties than their parent strains. As outlined above, we hypothesize that defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause IE. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Infective endocarditis (IE) is a rare but life-threatening infection. In the United States and western Europe, the incidence of community-acquired native-valve endocarditis is 2.0–6.2 cases per 100,000 people/year [1,2]. The epidemiologic features of IE in developed countries are changing as a result of increasing longevity, new predisposing factors, and an increase in nosocomial cases. The median age is 30–40 years during the preantibiotic era and 47–69 years recently [3]. The development of IE is the net result of the complex interaction between the bloodstream pathogen with matrix molecules and platelets at sites of endocardial cell damage. The following sequence of events is thought to result in IE: formation of nonbacterial thrombotic endocarditis (NBTE) on the surface of a cardiac valve or elsewhere that endothelial damage occurs, bacteremia, adherence of the bacteria in the bloodstream to NBTE and proliferation of bacteria within a vegetation. Accumulated evidence suggests that oral bacterial pathogens are associated with IE [4]. The association is speculated to be initiated by transient or prolonged bacteremia caused by oral bacteria. * Corresponding author. Tel./fax: +86 28 85503469. E-mail address: [email protected] (Y. Hao). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.05.018
Professional dental treatments and daily oral care such as tooth brushing and flossing, as well as food chewing possibly induce dissemination of oral bacteria into the bloodstream [5]. In 26 studies published between 1993 and 2003, 3784 cases of IE were presented, in which oral streptococci were considered to be involved in 21%, second highest in frequency to Staphylococcus aureus [6]. According to a review of 848 IE cases in Japan, the most common type of micro-organism isolated from patient samples was Grampositive streptococci (93.1%), among which oral streptococci were frequently detected at a prevalence of 38.6% [7]. Despite daily oral activities as well as professional dental treatments inducing bacteremia and the dental bacteremia as a risk factor of IE, detailed mechanism of dental bacteria in the pathogenesis of IE is far from elucidation to date. It is generally accepted that odontogenic bacteremias are shortlived and transient in nature and bacteria are scavenged from the bloodstream relatively quickly by the innate and adaptive defense mechanisms [8,9]. However, some studies indicate that an episode of odontogenic bacteremia could last as long as 60 min [10,11]. Recent studies suggest that amoxicillin therapy has a statistically significant impact on reducing the incidence, nature and duration of bacteremia from dental procedures, but it does not eliminate bacteremia [12]. How a few bacteria survive host defenses or escape from antibiotic attacking need to be evaluated further, as
1056
J. Lu et al. / Medical Hypotheses 73 (2009) 1055–1057
they may well be the ones that evade the initial host immune burst and have the propensity to seed target organs and cause systemic and distant infections [13,14]. There are two frequent routes of bacterial entry from teeth into the systemic circulation: the root canal or periapical lesions and the periodontium [15]. It seems logical to assume that Gram-negative microorganisms, commonly responsible for periodontal disease and periapical lesions, frequently enter the bloodstream as well as Gram-positive streptococcus spp., which comprises the main bacteria flora of cavity, but the fact is that Gram-negative oral bacteria rarely cause IE [16]. What is cell wall-deficient bacteria? The presence of cell wall-deficient bacteria (CWDB) has been noted for over a century, but, as yet, we still lack clarity about the fundamental nature of these organisms, such as their definition, basic cell biology or means of propagation. There is no universal agreement on the definition of CWDB. In general, CWDB may be defined as bacteria with altered morphology and cultural characteristics consistent with damaged or absent cell wall structures [17]. These atypical organisms may occur naturally or can be induced in the laboratory. The pleomorphic bacterial forms may revert or be stabilized when the inducing agent is removed. The term L-form refers to bacteria without a cell wall in vitro that grow on solid media treated with penicillin and propagated in a characteristic manner. Klieneberger originally used the term L-form in honour of the Lister institute while working there. Little is known about CWDB’s basic cell biology or their means of propagation. Early biochemical experiments indicated that stable L-forms of Gram-positive bacteria do not synthesize detectable amounts of peptidoglycan [18,19], D’Ari and co-workers have recently reported that Escherichia coli L-forms require residual peptidoglycan for division [20]. More recently, Leaver et al. has developed a controllable system for generating L-forms in the highly tractable model bacterium Bacillus subtilis. They proved that L-forms do not require peptidoglycan for division and that propagation of L-forms does not require the normal FtsZ-dependent division machine but occurs by a remarkable extrusion–resolution mechanism [21]. There is a widespread belief that CWDB may represent a response by the walled organism to adverse extracellular conditions like antibiotic pressure. The true relevance of CWDB to disease is unknown. A number of case reports and laboratory studies suggest its association with some diseases [22], and most commonly, IE has been reviewed extensively. Relevance of CWDB to IE CWDB may be found in the peripheral blood of patients with IE [23,24], and may also be demonstrated in vegetations on the valves of patients with IE [25]. Negative blood cultures may co-exist with the presence of CWDB in valvular vegetations. In one series, a total of 246 patients had a presumptive diagnosis of IE. The yield of 34% positive blood cultures in Todd–Hewitt broth increased to 51% in osmotically normal semi-liquid agar with 0.2% thioglycollate, and further increased to 81.2% in the yolk sacs of non-embryonated hen’s eggs. The investigators concluded that the requirement for osmotic support improved the yield of culture positive results and that CWDB may be present in infective endocarditis [26,27]. Wall-associated protein deficient of S. mutans involve in IE Streptococcus mutans (S. mutans), a major cariogenic bacterium, is occasionally isolated from the blood of patients with bactere-
mia and IE. Some wall-associated protein, such as three types of glucosyltransferase (GtfB, GtfC and GtfD), glucan-binding proteinthree-beamC (GbpC), biofilm regulatory protein A (BrpA) and cell surface protein antigen c (PAc), are main cariogenic virulence of S. mutans. The potential relevance of the cariogenic virulence to IE has been discussed. It was reported that strains from the heart valve lacked the three types of intact GTF, and the isolates from the heart valve were less susceptible to erythromycin and kanamycin [28] In addition, a GbpC-defective mutant strain, a BrpAdefective isogenic mutant strain and a PAc-defective mutant strain were significantly less susceptible to phagocytosis by human polymorphonuclear leukocytes than their parent strains. Further, a BrpA-defective mutant strain was found to possess higher platelet aggregation properties than its parent and injection of BrpA-defective or PAc-defective mutant strain into the jugular vein of specific pathogen-free Sprague–Dawley rats resulted in a longer duration of bacteremia; These results indicate that mutant strain is associated with virulence in blood, due to its correlation to phagocytosis susceptibility and platelet aggregation properties [29–31].
Hypothesis and explanation As outlined above, a hypothesis is formulated that defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause IE. Some unclear details related to the association between oral bacteria and IE may be explained by the hypothesis. Bacteria in oral cavity, an entrance of the alimentary canal, are easily affected by extraneous administration. Furthermore, there is an inherent deference in oral cavity to anti-bacteria such as lysozyme. We believe that any factors that act on cell wall may induce the damage of cell wall in bacteria, and that the damage of oral bacterial cell wall may occur in mouth naturally or can be induced in blood circulation by antibiotics. Because of the deficient of some cell wall components in bacteria, the antibiotics lose the specific bonds and the human polymorphonuclear leukocytes fail to recognize them, so odontogenic bacteria could survive in blood for an extended period and even have a chance attacking distant organs. The cell wall of the Gram-negative bacterium mainly consists of an outer membrane of lipopolysaccharide plus an inner peptidoglycan layer, while the cell wall of the Gram-positive bacterium is mainly made from a layer of peptidoglycan 50–100 molecules thick. It is well known that some antibiotics usually act by inhibiting the biosynthesis of peptidoglycan. Thus, in the human body the development of CWDB in Gram-positive organisms would preferentially be induced compared with Gram-negative bacteria. Further, Gram-positive bacteria frequently survive in blood circulation and cause IE. We question the traditional definition that CWDB should be shown by EM. We believe that the magnitude of cell wall deficiency may attribute to its recognition by EM. If cell wall deficiency is not enough to cause altered morphology, bacteria can not be recognized by EM, but they are really deficient in cell wall, and may be identified by other techniques such as molecular biology methods. We also believe that the magnitude of cell wall deficiency may vary from inducing factors and bacteria and it is the diversity of deficient magnitude, at least in part, that makes CWDB disaccord with previous studies. The result from molecular biology analysis on cell wall of bacteria in oral cavity, bloodstream with bacteremia, and at sites of endocardial valve may reveal interesting findings and prove our hypotheses. We believe our hypotheses may have a significant impact on understanding the relevance of oral bacteria to IE as well as systemic or end organ affections secondary to odontogenic bacteremia.
J. Lu et al. / Medical Hypotheses 73 (2009) 1055–1057
Acknowledgment We are grateful to Linlan MA for his assistance with review in English. References [1] Berlin JA, Abrutyn E, Strom BL, et al. Incidence of infective endocarditis in the Delaware Valley, 1988–1990. Am J Cardiol 1995;76:933–6. [2] Glennon PE, Head CEG, Roberts PR, Walker HA. Infective diseases of the heart. Cardiology. In: Firth JD, Polkey MI, Roberts PR, editors. Medical masterclass: cardiology and respiratory medicine. London: Royal College of Physicians of London, Blackwell Science; 2001. p. 92–4. [3] Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980–1990: a review of 210 episodes. Medicine (Baltimore) 1993;72:90–102. [4] Li X, Kolltveit KM, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev 2000;13:547–58. [5] Seymour RA, Lowry R, Whitworth JM, Martin MV. Infective endocarditis, dentistry and antibiotic prophylaxis; time for a rethink? Brit Dent J 2000;189: 610–6. [6] Moreillon P, Que YA. Infective endocarditis. Lancet 2004;363:139–49. [7] Nakatani S, Mitsutake K, Hozumi T, et al. Current characteristics of infective endocarditis in Japan: an analysis of 848 cases in 2000 and 2001. Circ J 2003;67:901–5. [8] Cates KL. Host factors in bacteremia. Am J Med 1983;75:19–25. [9] Petrunov B, Marinova S, Markova R, et al. Cellular and humoral systemic and mucosal immune responses stimulated in volunteers by an oral polybacterial immunomodulator ‘‘Dentavax”. Int Immunopharmacol 2006;6: 1181–93. [10] Roberts GJ, Jaffray EC, Spratt DA, et al. Duration, prevalence and intensity of bacteraemia after dental extractions in children. Heart 2006;92:1274–7. [11] Tomás I, Alvarez M, Limeres J, Potel C, Medina J, Diz P. Prevalence, duration and aetiology of bacteraemia following dental extractions. Oral Dis 2007;13: 56–62. [12] Lockhart PB, Brennan MT, Kent ML, Norton HJ, Weinrib DA. Impact of amoxicillin prophylaxis on the incidence, nature, and duration of bacteremia in children after intubation and dental procedures. Circulation 2004;109: 2878–84. [13] del Pozo JL, Patel R. The challenge of treating biofilm associated bacterial infections. Clin Pharmacol Ther 2007;82:204–9. [14] Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol 2007;5:48–56.
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[15] Parahitiyawa NB, Jin LJ, Leung WK, Yam WC, Samaranayake LP. Microbiology of odontogenic bacteremia: beyond endocarditis. Clin Microbiol Rev 2009;22: 46–64. [16] Pallasch TJ. Antibiotic prophylaxis: problems in paradise. Dent Clin North Am 2003;47:665–79. [17] Charache P. Cell wall-defective bacterial variants in human disease. Ann N Y Acad Sci 1970;174:903–11. [18] Ward JB. Peptidoglycan synthesis in L-phase variants of Bacillus licheniformis and Bacillus subtilis. J Bacteriol 1975;124:668–78. [19] King JR, Prescott B, Caldes G. Lack of murein in a formamide-insoluble fraction from the stable L-form of Streptococcus faecium. J Bacteriol 1970;102:196–7. [20] Joseleau-Petit D, Liébart JC, Ayala JA, D’Ari R. Unstable Escherichia coli L-forms revisited: growth requires peptidoglycan synthesis. J Bacteriol 2007;189: 6512–20. [21] Leaver M, Domínguez-Cuevas P, Coxhead JM, Daniel RA, Errington J. Life without a wall or division machine in Bacillus subtilis. Nature 2009;457: 849–53. [22] Onwuamaegbu ME, Belcher RA, Soare C. Cell wall-deficient bacteria as a cause of infections: a review of the clinical significance. J Int Med Res 2005;33:1–20. [23] Kagan GY, Mikhailova VS. Isolation of L-forms of streptococci from blood of patients with rheumatism and endocarditis. J Hyg Epidemiol Microbiol Immunol 1963;13:327–43. [24] Louria DB. L forms, spheroplasts and aberrant forms in chronic sepsis. Adv Int Med 1971;17:125–42. [25] Piepkorn MW, Reichenbach DD. Infective endocarditis associated with cell wall-deficient bacteria. Electron microscopic findings in four cases. Human Pathol 1978;9:163–73. [26] Wittler RG, Malizia WF, Kramer PE, Tuckett JD, Pritchard HN, Baker HJ. Isolation of a Corynebacterium and its transitional forms from a case of subacute bacterial endocarditis treated with antibiotics. J Gen Microbiol 1960;23:315–33. [27] Bouvet A, Ryter A, Frehel C, Acar JF. Nutritionally deficient Streptococci: electron microscopic study of 14 strains isolated in bacterial endocarditis. Ann Micribiol (Paris) 1980;131B:101–20. [28] Nomura R, Nakano K, Nemoto H, et al. Isolation and characterization of Streptococcus mutans in heart valve and dental plaque specimens from a patient with infective endocarditis. J Med Microbiol 2006;55:1135–40. [29] Nomura R, Nakano K, Ooshima T. Contribution of glucan-binding protein C of Streptococcus mutans to bacteremia occurrence. Arch Oral Biol 2004;49:783–8. [30] Nakano K, Fujita K, Nishimura K, Nomura R, Ooshima T. Contribution of biofilm regulatory protein A of Streptococcus mutans, to systemic virulence. Microbes Infect 2005;7:1246–55. [31] Nakano K, Tsuji M, Nishimura K, Nomura R, Ooshima T. Contribution of cell surface protein antigen PAc of Streptococcus mutans to bacteremia. Microbes Infect 2006;8:114–21.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause infective endocarditis Junjun Lu, Wenzhen Zhang, Yuqing Hao *, Yunwo Zhu State Key Laboratory of Oral Diseases, Sichuan University, No. 14, 3rd Section Renmin South Road, Chengdu, Sichuan 610041, China
a r t i c l e
i n f o
Article history: Received 5 May 2009 Accepted 10 May 2009
s u m m a r y Infective endocarditis (IE) is a rare but life-threatening infection. Bacteremia with organisms known to cause IE occurs commonly in association with invasive dental origin. Despite daily oral activities as well as professional dental treatments inducing bacteremia and the dental bacteremia as a risk factor of IE, the details of dental bacteria in the pathogenesis of IE are far from elucidation to date. How do a few microorganisms survive host defenses or escape from antibiotic attacking to seed target organs and cause distant infections? Why are Gram-positive bacteria more frequently detected than Gram-negative bacteria in IE? Cell wall-deficient bacteria (CWDB) were traditionally defined as bacteria with altered morphology and consistent with damaged or absent cell wall structures identified by EM. A number of case reports and laboratory studies suggest that CWDB may be found in the peripheral blood of patients with IE, and may also be demonstrated in vegetations on the valves of patients with IE. CWDB, in vitro, are resistant to antibiotics that act on cell wall biosynthesis. Recent studies indicate that the Streptococcus mutans (S. mutans) strains, the major cariogenic bacterium, isolated from the infected valve were deficient in some wall-associated proteins which are main cariogenic virulence of S. mutans, and the deficient stains exhibited less susceptible to antibiotics that act on cell wall biosynthesis. Further, the cloned deficient mutans were less susceptible to phagocytosis by human polymorphonuclear leukocytes but to possess higher platelet aggregation properties than their parent strains. As outlined above, we hypothesize that defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause IE. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Infective endocarditis (IE) is a rare but life-threatening infection. In the United States and western Europe, the incidence of community-acquired native-valve endocarditis is 2.0–6.2 cases per 100,000 people/year [1,2]. The epidemiologic features of IE in developed countries are changing as a result of increasing longevity, new predisposing factors, and an increase in nosocomial cases. The median age is 30–40 years during the preantibiotic era and 47–69 years recently [3]. The development of IE is the net result of the complex interaction between the bloodstream pathogen with matrix molecules and platelets at sites of endocardial cell damage. The following sequence of events is thought to result in IE: formation of nonbacterial thrombotic endocarditis (NBTE) on the surface of a cardiac valve or elsewhere that endothelial damage occurs, bacteremia, adherence of the bacteria in the bloodstream to NBTE and proliferation of bacteria within a vegetation. Accumulated evidence suggests that oral bacterial pathogens are associated with IE [4]. The association is speculated to be initiated by transient or prolonged bacteremia caused by oral bacteria. * Corresponding author. Tel./fax: +86 28 85503469. E-mail address: [email protected] (Y. Hao). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.05.018
Professional dental treatments and daily oral care such as tooth brushing and flossing, as well as food chewing possibly induce dissemination of oral bacteria into the bloodstream [5]. In 26 studies published between 1993 and 2003, 3784 cases of IE were presented, in which oral streptococci were considered to be involved in 21%, second highest in frequency to Staphylococcus aureus [6]. According to a review of 848 IE cases in Japan, the most common type of micro-organism isolated from patient samples was Grampositive streptococci (93.1%), among which oral streptococci were frequently detected at a prevalence of 38.6% [7]. Despite daily oral activities as well as professional dental treatments inducing bacteremia and the dental bacteremia as a risk factor of IE, detailed mechanism of dental bacteria in the pathogenesis of IE is far from elucidation to date. It is generally accepted that odontogenic bacteremias are shortlived and transient in nature and bacteria are scavenged from the bloodstream relatively quickly by the innate and adaptive defense mechanisms [8,9]. However, some studies indicate that an episode of odontogenic bacteremia could last as long as 60 min [10,11]. Recent studies suggest that amoxicillin therapy has a statistically significant impact on reducing the incidence, nature and duration of bacteremia from dental procedures, but it does not eliminate bacteremia [12]. How a few bacteria survive host defenses or escape from antibiotic attacking need to be evaluated further, as
1056
J. Lu et al. / Medical Hypotheses 73 (2009) 1055–1057
they may well be the ones that evade the initial host immune burst and have the propensity to seed target organs and cause systemic and distant infections [13,14]. There are two frequent routes of bacterial entry from teeth into the systemic circulation: the root canal or periapical lesions and the periodontium [15]. It seems logical to assume that Gram-negative microorganisms, commonly responsible for periodontal disease and periapical lesions, frequently enter the bloodstream as well as Gram-positive streptococcus spp., which comprises the main bacteria flora of cavity, but the fact is that Gram-negative oral bacteria rarely cause IE [16]. What is cell wall-deficient bacteria? The presence of cell wall-deficient bacteria (CWDB) has been noted for over a century, but, as yet, we still lack clarity about the fundamental nature of these organisms, such as their definition, basic cell biology or means of propagation. There is no universal agreement on the definition of CWDB. In general, CWDB may be defined as bacteria with altered morphology and cultural characteristics consistent with damaged or absent cell wall structures [17]. These atypical organisms may occur naturally or can be induced in the laboratory. The pleomorphic bacterial forms may revert or be stabilized when the inducing agent is removed. The term L-form refers to bacteria without a cell wall in vitro that grow on solid media treated with penicillin and propagated in a characteristic manner. Klieneberger originally used the term L-form in honour of the Lister institute while working there. Little is known about CWDB’s basic cell biology or their means of propagation. Early biochemical experiments indicated that stable L-forms of Gram-positive bacteria do not synthesize detectable amounts of peptidoglycan [18,19], D’Ari and co-workers have recently reported that Escherichia coli L-forms require residual peptidoglycan for division [20]. More recently, Leaver et al. has developed a controllable system for generating L-forms in the highly tractable model bacterium Bacillus subtilis. They proved that L-forms do not require peptidoglycan for division and that propagation of L-forms does not require the normal FtsZ-dependent division machine but occurs by a remarkable extrusion–resolution mechanism [21]. There is a widespread belief that CWDB may represent a response by the walled organism to adverse extracellular conditions like antibiotic pressure. The true relevance of CWDB to disease is unknown. A number of case reports and laboratory studies suggest its association with some diseases [22], and most commonly, IE has been reviewed extensively. Relevance of CWDB to IE CWDB may be found in the peripheral blood of patients with IE [23,24], and may also be demonstrated in vegetations on the valves of patients with IE [25]. Negative blood cultures may co-exist with the presence of CWDB in valvular vegetations. In one series, a total of 246 patients had a presumptive diagnosis of IE. The yield of 34% positive blood cultures in Todd–Hewitt broth increased to 51% in osmotically normal semi-liquid agar with 0.2% thioglycollate, and further increased to 81.2% in the yolk sacs of non-embryonated hen’s eggs. The investigators concluded that the requirement for osmotic support improved the yield of culture positive results and that CWDB may be present in infective endocarditis [26,27]. Wall-associated protein deficient of S. mutans involve in IE Streptococcus mutans (S. mutans), a major cariogenic bacterium, is occasionally isolated from the blood of patients with bactere-
mia and IE. Some wall-associated protein, such as three types of glucosyltransferase (GtfB, GtfC and GtfD), glucan-binding proteinthree-beamC (GbpC), biofilm regulatory protein A (BrpA) and cell surface protein antigen c (PAc), are main cariogenic virulence of S. mutans. The potential relevance of the cariogenic virulence to IE has been discussed. It was reported that strains from the heart valve lacked the three types of intact GTF, and the isolates from the heart valve were less susceptible to erythromycin and kanamycin [28] In addition, a GbpC-defective mutant strain, a BrpAdefective isogenic mutant strain and a PAc-defective mutant strain were significantly less susceptible to phagocytosis by human polymorphonuclear leukocytes than their parent strains. Further, a BrpA-defective mutant strain was found to possess higher platelet aggregation properties than its parent and injection of BrpA-defective or PAc-defective mutant strain into the jugular vein of specific pathogen-free Sprague–Dawley rats resulted in a longer duration of bacteremia; These results indicate that mutant strain is associated with virulence in blood, due to its correlation to phagocytosis susceptibility and platelet aggregation properties [29–31].
Hypothesis and explanation As outlined above, a hypothesis is formulated that defect of cell wall construction may shield oral bacteria’s survival in bloodstream and cause IE. Some unclear details related to the association between oral bacteria and IE may be explained by the hypothesis. Bacteria in oral cavity, an entrance of the alimentary canal, are easily affected by extraneous administration. Furthermore, there is an inherent deference in oral cavity to anti-bacteria such as lysozyme. We believe that any factors that act on cell wall may induce the damage of cell wall in bacteria, and that the damage of oral bacterial cell wall may occur in mouth naturally or can be induced in blood circulation by antibiotics. Because of the deficient of some cell wall components in bacteria, the antibiotics lose the specific bonds and the human polymorphonuclear leukocytes fail to recognize them, so odontogenic bacteria could survive in blood for an extended period and even have a chance attacking distant organs. The cell wall of the Gram-negative bacterium mainly consists of an outer membrane of lipopolysaccharide plus an inner peptidoglycan layer, while the cell wall of the Gram-positive bacterium is mainly made from a layer of peptidoglycan 50–100 molecules thick. It is well known that some antibiotics usually act by inhibiting the biosynthesis of peptidoglycan. Thus, in the human body the development of CWDB in Gram-positive organisms would preferentially be induced compared with Gram-negative bacteria. Further, Gram-positive bacteria frequently survive in blood circulation and cause IE. We question the traditional definition that CWDB should be shown by EM. We believe that the magnitude of cell wall deficiency may attribute to its recognition by EM. If cell wall deficiency is not enough to cause altered morphology, bacteria can not be recognized by EM, but they are really deficient in cell wall, and may be identified by other techniques such as molecular biology methods. We also believe that the magnitude of cell wall deficiency may vary from inducing factors and bacteria and it is the diversity of deficient magnitude, at least in part, that makes CWDB disaccord with previous studies. The result from molecular biology analysis on cell wall of bacteria in oral cavity, bloodstream with bacteremia, and at sites of endocardial valve may reveal interesting findings and prove our hypotheses. We believe our hypotheses may have a significant impact on understanding the relevance of oral bacteria to IE as well as systemic or end organ affections secondary to odontogenic bacteremia.
J. Lu et al. / Medical Hypotheses 73 (2009) 1055–1057
Acknowledgment We are grateful to Linlan MA for his assistance with review in English. References [1] Berlin JA, Abrutyn E, Strom BL, et al. Incidence of infective endocarditis in the Delaware Valley, 1988–1990. Am J Cardiol 1995;76:933–6. [2] Glennon PE, Head CEG, Roberts PR, Walker HA. Infective diseases of the heart. Cardiology. In: Firth JD, Polkey MI, Roberts PR, editors. Medical masterclass: cardiology and respiratory medicine. London: Royal College of Physicians of London, Blackwell Science; 2001. p. 92–4. [3] Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980–1990: a review of 210 episodes. Medicine (Baltimore) 1993;72:90–102. [4] Li X, Kolltveit KM, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev 2000;13:547–58. [5] Seymour RA, Lowry R, Whitworth JM, Martin MV. Infective endocarditis, dentistry and antibiotic prophylaxis; time for a rethink? Brit Dent J 2000;189: 610–6. [6] Moreillon P, Que YA. Infective endocarditis. Lancet 2004;363:139–49. [7] Nakatani S, Mitsutake K, Hozumi T, et al. Current characteristics of infective endocarditis in Japan: an analysis of 848 cases in 2000 and 2001. Circ J 2003;67:901–5. [8] Cates KL. Host factors in bacteremia. Am J Med 1983;75:19–25. [9] Petrunov B, Marinova S, Markova R, et al. Cellular and humoral systemic and mucosal immune responses stimulated in volunteers by an oral polybacterial immunomodulator ‘‘Dentavax”. Int Immunopharmacol 2006;6: 1181–93. [10] Roberts GJ, Jaffray EC, Spratt DA, et al. Duration, prevalence and intensity of bacteraemia after dental extractions in children. Heart 2006;92:1274–7. [11] Tomás I, Alvarez M, Limeres J, Potel C, Medina J, Diz P. Prevalence, duration and aetiology of bacteraemia following dental extractions. Oral Dis 2007;13: 56–62. [12] Lockhart PB, Brennan MT, Kent ML, Norton HJ, Weinrib DA. Impact of amoxicillin prophylaxis on the incidence, nature, and duration of bacteremia in children after intubation and dental procedures. Circulation 2004;109: 2878–84. [13] del Pozo JL, Patel R. The challenge of treating biofilm associated bacterial infections. Clin Pharmacol Ther 2007;82:204–9. [14] Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol 2007;5:48–56.
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[15] Parahitiyawa NB, Jin LJ, Leung WK, Yam WC, Samaranayake LP. Microbiology of odontogenic bacteremia: beyond endocarditis. Clin Microbiol Rev 2009;22: 46–64. [16] Pallasch TJ. Antibiotic prophylaxis: problems in paradise. Dent Clin North Am 2003;47:665–79. [17] Charache P. Cell wall-defective bacterial variants in human disease. Ann N Y Acad Sci 1970;174:903–11. [18] Ward JB. Peptidoglycan synthesis in L-phase variants of Bacillus licheniformis and Bacillus subtilis. J Bacteriol 1975;124:668–78. [19] King JR, Prescott B, Caldes G. Lack of murein in a formamide-insoluble fraction from the stable L-form of Streptococcus faecium. J Bacteriol 1970;102:196–7. [20] Joseleau-Petit D, Liébart JC, Ayala JA, D’Ari R. Unstable Escherichia coli L-forms revisited: growth requires peptidoglycan synthesis. J Bacteriol 2007;189: 6512–20. [21] Leaver M, Domínguez-Cuevas P, Coxhead JM, Daniel RA, Errington J. Life without a wall or division machine in Bacillus subtilis. Nature 2009;457: 849–53. [22] Onwuamaegbu ME, Belcher RA, Soare C. Cell wall-deficient bacteria as a cause of infections: a review of the clinical significance. J Int Med Res 2005;33:1–20. [23] Kagan GY, Mikhailova VS. Isolation of L-forms of streptococci from blood of patients with rheumatism and endocarditis. J Hyg Epidemiol Microbiol Immunol 1963;13:327–43. [24] Louria DB. L forms, spheroplasts and aberrant forms in chronic sepsis. Adv Int Med 1971;17:125–42. [25] Piepkorn MW, Reichenbach DD. Infective endocarditis associated with cell wall-deficient bacteria. Electron microscopic findings in four cases. Human Pathol 1978;9:163–73. [26] Wittler RG, Malizia WF, Kramer PE, Tuckett JD, Pritchard HN, Baker HJ. Isolation of a Corynebacterium and its transitional forms from a case of subacute bacterial endocarditis treated with antibiotics. J Gen Microbiol 1960;23:315–33. [27] Bouvet A, Ryter A, Frehel C, Acar JF. Nutritionally deficient Streptococci: electron microscopic study of 14 strains isolated in bacterial endocarditis. Ann Micribiol (Paris) 1980;131B:101–20. [28] Nomura R, Nakano K, Nemoto H, et al. Isolation and characterization of Streptococcus mutans in heart valve and dental plaque specimens from a patient with infective endocarditis. J Med Microbiol 2006;55:1135–40. [29] Nomura R, Nakano K, Ooshima T. Contribution of glucan-binding protein C of Streptococcus mutans to bacteremia occurrence. Arch Oral Biol 2004;49:783–8. [30] Nakano K, Fujita K, Nishimura K, Nomura R, Ooshima T. Contribution of biofilm regulatory protein A of Streptococcus mutans, to systemic virulence. Microbes Infect 2005;7:1246–55. [31] Nakano K, Tsuji M, Nishimura K, Nomura R, Ooshima T. Contribution of cell surface protein antigen PAc of Streptococcus mutans to bacteremia. Microbes Infect 2006;8:114–21.