EDITORIAL For reprint orders, please contact: [email protected]
Candida albicans and Streptococcus mutans: a potential synergistic alliance to cause virulent tooth decay in children “...the available evidence prompts
Hyun Koo*,1,2 & William H Bowen3
Dental caries represents one of the most prevalent and costly biofilm-dependent diseases that afflict children and adults worldwide [1] . The disease, manifested clinically as cavities, is a prime example of the consequences arising from interactions on (tooth) surfaces between microorganisms, microbial products, host (saliva) and diet (sugar), leading to the establishment of pathogenic biofilms, or dental plaque, that causes tooth decay. Early childhood caries (ECC) is a particularly virulent type of tooth decay that most frequently afflicts underprivileged preschool children [1] . The onset and progression of carious lesions in ECC is rapid and aggressive, resulting in rampant destruction of the smooth surfaces of teeth; they are painful, recurring and frequently require surgery under general anesthesia. It is an extremely expensive disease to treat and constitutes a major challenge in public health [1] . Streptococcus mutans has been ascribed as the primary microbial culprit of ECC through its heavy presence in the biofilms
the possibility of incorporating anti-Candida therapy in the treatment of early childhood caries and reiterates the need to develop effective agents to inhibit glucosyltransferases. ” formed on the tooth surface (albeit additional bacteria may be also involved with the pathogenesis of dental caries) [2–4] . In addition to heavy infection by S. mutans, the plaque collected from caries-active children is also particularly rich in extracellular polysaccharides. Furthermore, it has long been recognized that diet (e.g., persistent exposure to sugars) plays a critical role in the etiology of ECC [1] . Many attribute virulence of S. mutans solely to its ability to produce acid and to tolerate an acidic environment. However, many organisms found in cariogenic dental plaque share these biological properties [5] . We believe that S. mutans’ s key virulence factor resides in its ability to convert dietary sucrose into a diverse range of soluble and, particularly, insoluble extracellular polysaccharides (EPS) through exoenzymes such as glucosyltransferases (Gtfs). The EPS are the prime building blocks of cariogenic biofilms. They promote the colonization of the tooth surface by S. mutans and the recruitment of additional microorganisms into dental plaque,
KEYWORDS
• biofilms • glucosyltransferases • Candida albicans • early childhood caries • exopolysaccharides • extracellular matrix • polymicrobial • Streptococcus mutans
“...our results suggest the need to explore how Candida infection is acquired and whether some strains are more infectious than others.”
Biofilm Research Labs, Levy Center for Oral Health Research, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 2 Department of Orthodontics & Divisions of Pediatric Dentistry & Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 3 Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA *Author for correspondence: [email protected] 1
10.2217/FMB.14.92 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(12), 1295–1297
part of
ISSN 1746-0913
1295
Editorial Koo & Bowen
“We suggest that the presence of abundant extracellular polysaccharides matrix (surrounding a dense population of acidogenic microbial cells) could effectively block access by saliva to the interior of the biofilm and/or prevent acid within biofilm from diffusing outward.”
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while forming the scaffold core or matrix of the biofilm [6] . In addition, EPS-rich matrix also creates a diffusion-limiting barrier, facilitating the creation of acidic microenvironments at the biofilm–tooth interface [6,7] , which are critical for the dissolution of the adjacent tooth enamel. Results from previous clinical studies reveal that, in addition to S. mutans, the fungus Candida albicans is frequently detected in high numbers in plaque-biofilms from toddlers with ECC [8–10] . This observation was intriguing because C. albicans usually does not associate well with S. mutans, nor does it colonize teeth effectively on its own or cause severe smoothsurface carious lesions in rodent models [11,12] . Rather, C. albicans adheres mainly to oral mucosa (e.g., cheek and tongue) as well as to acrylic surfaces (such as those found in some dental prosthesis), while interacting with commensal streptococci (e.g., Streptococcus gordonii, S. oralis) to cause mucosal infections [13,14] . Furthermore, Candida usually does not metabolize sucrose efficiently which of course added to the enigma. Evidence from prior in vitro studies revealed that the adhesive interactions between S. mutans and C. albicans may be enhanced in the presence of sucrose [15,16] , while promoting mixed-species biofilm formation [17,18] . Images derived from scanning electron microscopy demonstrated extracellular material formed between streptococci and yeast cells [15,18] , suggesting that glucans play a role in mediating binding to each other and the development of mixedspecies biofilms when grown in sucrose. Indeed, using purified Gtf enzymes, we demonstrated that glucans formed in situ by GtfB greatly enhances co-adherence between S. mutans and C. albicans cells while simultaneously facilitating fungal adhesion to saliva-coated apatitic surfaces in vitro [16] . Collectively, these observations can explain at least in part why C. albicans are found together with S. mutans in plaque-biofilms associated with ECC. Although C. albicans is detected commonly in plaque from patients with ECC, their role if any in the pathogenesis of the disease has remained puzzling. Recently, we have observed an extraordinary synergistic interaction between C. albicans and S. mutans mediated through the influence of bacterially derived Gtfs exoenzymes [12] . We have determined that S. mutans Gtfs (particularly GtfB) binds to the surface of C. albicans cells even when they are in hyphal form thereby converting them into de facto glucan producers
Future Microbiol. (2014) 9(12)
when sucrose is available. This unique interaction results in an enormous increase in the amount of EPS in the biofilm matrix, and synergistically enhances the expression of virulence in vivo as determined using a rodent model of dental caries [12] . In our animal model and as noticed in patients with ECC, many of the carious lesions occur on the free smooth surfaces of the teeth. We found a dramatic increase in the number and severity of smooth-surface lesions in the dually infected animals compared with singly infected animals [12] . This striking in vivo evidence supports the concept that ECC in toddlers may actually result from infection by both organisms together with overexposure to sucrose. Most commonly, lesions occur on the biting (fissure) surface of molars except under exceptional circumstance, for example, when access by saliva to tooth surfaces is restricted. We observed that the combination of S. mutans and Candida dramatically modifies the physical environment of the biofilms by enhancing the amounts of highly insoluble and diffusion-limiting glucan, thereby increasing the bulk of the biofilms and the density of infection [12] . We suggest that the presence of abundant EPS matrix (surrounding a dense population of acidogenic microbial cells) could effectively block access by saliva to the interior of the biofilm and/or prevent acid within biofilm from diffusing outward [7,12] . This phenomenon would ensure that the acid formed within the biofilm would remain unneutralized and lead to a protracted acid dissolution of the enamel. Clearly, we have identified a novel and truly unique physical interaction where a bacterially produced exoenzyme adheres to, and functions on, the surface of an organism from another kingdom, transforming it into a fierce stimulator of cariogenic biofilm formation. It is also conceivable that acid production by the combination of S. mutans and C. albicans was enhanced, as the fungus is highly acidogenic [11] . Furthermore, the presence of these organisms together within biofilm could also induce additional responses in one another [12,19] . Whether other factors such as signaling interactors [19] mediate this synergistic cross-kingdom interaction to influence the pathogenesis of dental caries remain to be elucidated in vivo. Previous human and in vitro studies combined with our recent in vivo work offer plausible data to support the clinical importance of the association between C. albicans and S. mutans in the pathogenesis of ECC; further longitudinal
future science group
Candida albicans–Streptococcus mutans interactions in dental caries disease and epidemiological studies are certainly worthy of exploration. Clearly, unusual combinations of organisms may generate biofilms with unique virulence properties and demonstrate the need to explore the interactions of mixed flora so frequently observed in medically relevant biofilms formed in vivo [20] . There is much to learn about the assembly principles, structure and physiology of mixed-species biofilms. Our observation serves once again to emphasize the critical role that the matrix plays in biofilm formation, architecture and expression of virulence. Furthermore, our results suggest the need to explore how Candida infection is acquired and whether some strains are more infectious than others. In addition, the available evidence prompts the possibility of References 1
Dye BA, Tan S, Smith V et al. Trends in oral health status: United States, 1988–1994 and 1999–2004. Vital Health Stat. 11 (248), 1–92 (2007).
2
Parisotto TM, Steiner-Oliveira C, Silva CM et al. Early childhood caries and mutans streptococci: a systematic review. Oral Health Prev. Dent. 8(1), 59–70 (2010).
3
Gross EL, Leys EJ, Gasparovich SR et al. Bacterial 16S sequence analysis of severe caries in young permanent teeth. J. Clin. Microbiol. 48(11), 4121–4128 (2010).
4
5
6
7
Hughes CV, Dahlan M, Papadopolou E et al. Aciduric microbiota and mutans streptococci in severe and recurrent severe early childhood caries. Pediatr. Dent. 34(2), e16–23 (2012). Nyvad B, Crielaard W, Mira A et al. Dental caries from a molecular microbiological perspective. Caries Res. 47(2), 89–102 (2013). Bowen WH, Koo H. Biology of Streptococcus mutans-derived glucosyltransferases: role in extracellular matrix formation of cariogenic biofilms. Caries Res. 45(1), 69–86 (2011). Xiao J, Klein MI, Falsetta ML et al. The exopolysaccharide matrix modulates the interaction between 3D architecture and virulence of a mixed-species oral biofilm. PLoS Pathog. 8 (4), e1002623 (2012).
future science group
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Editorial
incorporating anti-Candida therapy in the treatment of ECC and reiterates the need to develop effective agents to inhibit Gtfs. Such approaches combined with effective use of fluoride could help to bring this costly and painful affliction under control. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
de Carvalho FG, Silva DS, Hebling J et al. Presence of mutans Streptococci and Candida spp. in dental plaque/dentine of carious teeth and early childhood caries. Arch. Oral Biol. 51(11), 1024–1028 (2006).
15 Branting C, Sund ML, Linder LE. The
Raja M, Hannan A, Ali K. Association of oral candidal carriage with dental caries in children. Caries Res. 44(3), 272–276 (2010).
16 Gregoire S, Xiao J, Silva BB et al. Role of
10 Yang XQ, Zhang Q, Lu LY et al. Genotypic
distribution of Candida albicans in dental biofilm of Chinese children associated with severe early childhood caries. Arch. Oral Biol. 57(8), 1048–1053 (2012). 11 Klinke T, Guggenheim B, Klimm W,
Thurnheer T. Dental caries in rats associated with Candida albicans. Caries Res. 45(2), 100–106 (2011). 12 Falsetta ML, Klein MI, Colonne PM et al.
Symbiotic relationship between Streptococcus mutans and Candida albicans synergizes virulence of plaque biofilms in vivo. Infect. Immun. 82(5), 1968–1981 (2014). 13 Thein ZM, Seneviratne CJ, Samaranayake
YH, Samaranayake LP. Community lifestyle of Candida in mixed biofilms: a mini review. Mycoses 52(6), 467–475 (2009). 14 Xu H, Jenkinson HF, Dongari-Bagtzoglou A.
Innocent until proven guilty: mechanisms and roles of Streptococcus–Candida interactions in oral health and disease. Mol. Oral Microbiol. 29(3), 99–116 (2014).
influence of Streptococcus mutans on adhesion of Candida albicans to acrylic surfaces in vitro. Arch. Oral Biol. 34(5), 347–353 (1989). glucosyltransferase B in the interactions of Candida albicans with Streptococcus mutans and experimental pellicle formed on hydroxyapatite surface. Appl. Environ. Microbiol. 77(18), 6357–6367 (2011). 17 Pereira-Cenci T, Deng DM, Kraneveld EA
et al. The effect of Streptococcus mutans and Candida glabrata on Candida albicans biofilms formed on different surfaces. Arch. Oral Biol. 53(8), 755–764 (2008). 18 Metwalli KH, Khan SA, Krom BP et al.
Streptococcus mutans, Candida albicans, and the human mouth: a sticky situation. PLoS Pathog. 9, e1003616 (2013). 19 Sztajer H, Szafranski SP, Tomasch J et al.
Cross-feeding and interkingdom communication in dual-species biofilms of Streptococcus mutans and Candida albicans. ISME J. doi:10.1038ismej.73 (2014) (Epub ahead of print). 20 Peleg AY, Hogan DA, Mylonakis E.
Medically important bacterial–fungal interactions. Nat. Rev. Microbiol. 8(5), 340–349 (2010).
www.futuremedicine.com
1297
Candida albicans and Streptococcus mutans: a potential synergistic alliance to cause virulent tooth decay in children “...the available evidence prompts
Hyun Koo*,1,2 & William H Bowen3
Dental caries represents one of the most prevalent and costly biofilm-dependent diseases that afflict children and adults worldwide [1] . The disease, manifested clinically as cavities, is a prime example of the consequences arising from interactions on (tooth) surfaces between microorganisms, microbial products, host (saliva) and diet (sugar), leading to the establishment of pathogenic biofilms, or dental plaque, that causes tooth decay. Early childhood caries (ECC) is a particularly virulent type of tooth decay that most frequently afflicts underprivileged preschool children [1] . The onset and progression of carious lesions in ECC is rapid and aggressive, resulting in rampant destruction of the smooth surfaces of teeth; they are painful, recurring and frequently require surgery under general anesthesia. It is an extremely expensive disease to treat and constitutes a major challenge in public health [1] . Streptococcus mutans has been ascribed as the primary microbial culprit of ECC through its heavy presence in the biofilms
the possibility of incorporating anti-Candida therapy in the treatment of early childhood caries and reiterates the need to develop effective agents to inhibit glucosyltransferases. ” formed on the tooth surface (albeit additional bacteria may be also involved with the pathogenesis of dental caries) [2–4] . In addition to heavy infection by S. mutans, the plaque collected from caries-active children is also particularly rich in extracellular polysaccharides. Furthermore, it has long been recognized that diet (e.g., persistent exposure to sugars) plays a critical role in the etiology of ECC [1] . Many attribute virulence of S. mutans solely to its ability to produce acid and to tolerate an acidic environment. However, many organisms found in cariogenic dental plaque share these biological properties [5] . We believe that S. mutans’ s key virulence factor resides in its ability to convert dietary sucrose into a diverse range of soluble and, particularly, insoluble extracellular polysaccharides (EPS) through exoenzymes such as glucosyltransferases (Gtfs). The EPS are the prime building blocks of cariogenic biofilms. They promote the colonization of the tooth surface by S. mutans and the recruitment of additional microorganisms into dental plaque,
KEYWORDS
• biofilms • glucosyltransferases • Candida albicans • early childhood caries • exopolysaccharides • extracellular matrix • polymicrobial • Streptococcus mutans
“...our results suggest the need to explore how Candida infection is acquired and whether some strains are more infectious than others.”
Biofilm Research Labs, Levy Center for Oral Health Research, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 2 Department of Orthodontics & Divisions of Pediatric Dentistry & Community Oral Health, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA 3 Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642, USA *Author for correspondence: [email protected] 1
10.2217/FMB.14.92 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(12), 1295–1297
part of
ISSN 1746-0913
1295
Editorial Koo & Bowen
“We suggest that the presence of abundant extracellular polysaccharides matrix (surrounding a dense population of acidogenic microbial cells) could effectively block access by saliva to the interior of the biofilm and/or prevent acid within biofilm from diffusing outward.”
1296
while forming the scaffold core or matrix of the biofilm [6] . In addition, EPS-rich matrix also creates a diffusion-limiting barrier, facilitating the creation of acidic microenvironments at the biofilm–tooth interface [6,7] , which are critical for the dissolution of the adjacent tooth enamel. Results from previous clinical studies reveal that, in addition to S. mutans, the fungus Candida albicans is frequently detected in high numbers in plaque-biofilms from toddlers with ECC [8–10] . This observation was intriguing because C. albicans usually does not associate well with S. mutans, nor does it colonize teeth effectively on its own or cause severe smoothsurface carious lesions in rodent models [11,12] . Rather, C. albicans adheres mainly to oral mucosa (e.g., cheek and tongue) as well as to acrylic surfaces (such as those found in some dental prosthesis), while interacting with commensal streptococci (e.g., Streptococcus gordonii, S. oralis) to cause mucosal infections [13,14] . Furthermore, Candida usually does not metabolize sucrose efficiently which of course added to the enigma. Evidence from prior in vitro studies revealed that the adhesive interactions between S. mutans and C. albicans may be enhanced in the presence of sucrose [15,16] , while promoting mixed-species biofilm formation [17,18] . Images derived from scanning electron microscopy demonstrated extracellular material formed between streptococci and yeast cells [15,18] , suggesting that glucans play a role in mediating binding to each other and the development of mixedspecies biofilms when grown in sucrose. Indeed, using purified Gtf enzymes, we demonstrated that glucans formed in situ by GtfB greatly enhances co-adherence between S. mutans and C. albicans cells while simultaneously facilitating fungal adhesion to saliva-coated apatitic surfaces in vitro [16] . Collectively, these observations can explain at least in part why C. albicans are found together with S. mutans in plaque-biofilms associated with ECC. Although C. albicans is detected commonly in plaque from patients with ECC, their role if any in the pathogenesis of the disease has remained puzzling. Recently, we have observed an extraordinary synergistic interaction between C. albicans and S. mutans mediated through the influence of bacterially derived Gtfs exoenzymes [12] . We have determined that S. mutans Gtfs (particularly GtfB) binds to the surface of C. albicans cells even when they are in hyphal form thereby converting them into de facto glucan producers
Future Microbiol. (2014) 9(12)
when sucrose is available. This unique interaction results in an enormous increase in the amount of EPS in the biofilm matrix, and synergistically enhances the expression of virulence in vivo as determined using a rodent model of dental caries [12] . In our animal model and as noticed in patients with ECC, many of the carious lesions occur on the free smooth surfaces of the teeth. We found a dramatic increase in the number and severity of smooth-surface lesions in the dually infected animals compared with singly infected animals [12] . This striking in vivo evidence supports the concept that ECC in toddlers may actually result from infection by both organisms together with overexposure to sucrose. Most commonly, lesions occur on the biting (fissure) surface of molars except under exceptional circumstance, for example, when access by saliva to tooth surfaces is restricted. We observed that the combination of S. mutans and Candida dramatically modifies the physical environment of the biofilms by enhancing the amounts of highly insoluble and diffusion-limiting glucan, thereby increasing the bulk of the biofilms and the density of infection [12] . We suggest that the presence of abundant EPS matrix (surrounding a dense population of acidogenic microbial cells) could effectively block access by saliva to the interior of the biofilm and/or prevent acid within biofilm from diffusing outward [7,12] . This phenomenon would ensure that the acid formed within the biofilm would remain unneutralized and lead to a protracted acid dissolution of the enamel. Clearly, we have identified a novel and truly unique physical interaction where a bacterially produced exoenzyme adheres to, and functions on, the surface of an organism from another kingdom, transforming it into a fierce stimulator of cariogenic biofilm formation. It is also conceivable that acid production by the combination of S. mutans and C. albicans was enhanced, as the fungus is highly acidogenic [11] . Furthermore, the presence of these organisms together within biofilm could also induce additional responses in one another [12,19] . Whether other factors such as signaling interactors [19] mediate this synergistic cross-kingdom interaction to influence the pathogenesis of dental caries remain to be elucidated in vivo. Previous human and in vitro studies combined with our recent in vivo work offer plausible data to support the clinical importance of the association between C. albicans and S. mutans in the pathogenesis of ECC; further longitudinal
future science group
Candida albicans–Streptococcus mutans interactions in dental caries disease and epidemiological studies are certainly worthy of exploration. Clearly, unusual combinations of organisms may generate biofilms with unique virulence properties and demonstrate the need to explore the interactions of mixed flora so frequently observed in medically relevant biofilms formed in vivo [20] . There is much to learn about the assembly principles, structure and physiology of mixed-species biofilms. Our observation serves once again to emphasize the critical role that the matrix plays in biofilm formation, architecture and expression of virulence. Furthermore, our results suggest the need to explore how Candida infection is acquired and whether some strains are more infectious than others. In addition, the available evidence prompts the possibility of References 1
Dye BA, Tan S, Smith V et al. Trends in oral health status: United States, 1988–1994 and 1999–2004. Vital Health Stat. 11 (248), 1–92 (2007).
2
Parisotto TM, Steiner-Oliveira C, Silva CM et al. Early childhood caries and mutans streptococci: a systematic review. Oral Health Prev. Dent. 8(1), 59–70 (2010).
3
Gross EL, Leys EJ, Gasparovich SR et al. Bacterial 16S sequence analysis of severe caries in young permanent teeth. J. Clin. Microbiol. 48(11), 4121–4128 (2010).
4
5
6
7
Hughes CV, Dahlan M, Papadopolou E et al. Aciduric microbiota and mutans streptococci in severe and recurrent severe early childhood caries. Pediatr. Dent. 34(2), e16–23 (2012). Nyvad B, Crielaard W, Mira A et al. Dental caries from a molecular microbiological perspective. Caries Res. 47(2), 89–102 (2013). Bowen WH, Koo H. Biology of Streptococcus mutans-derived glucosyltransferases: role in extracellular matrix formation of cariogenic biofilms. Caries Res. 45(1), 69–86 (2011). Xiao J, Klein MI, Falsetta ML et al. The exopolysaccharide matrix modulates the interaction between 3D architecture and virulence of a mixed-species oral biofilm. PLoS Pathog. 8 (4), e1002623 (2012).
future science group
8
9
Editorial
incorporating anti-Candida therapy in the treatment of ECC and reiterates the need to develop effective agents to inhibit Gtfs. Such approaches combined with effective use of fluoride could help to bring this costly and painful affliction under control. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
de Carvalho FG, Silva DS, Hebling J et al. Presence of mutans Streptococci and Candida spp. in dental plaque/dentine of carious teeth and early childhood caries. Arch. Oral Biol. 51(11), 1024–1028 (2006).
15 Branting C, Sund ML, Linder LE. The
Raja M, Hannan A, Ali K. Association of oral candidal carriage with dental caries in children. Caries Res. 44(3), 272–276 (2010).
16 Gregoire S, Xiao J, Silva BB et al. Role of
10 Yang XQ, Zhang Q, Lu LY et al. Genotypic
distribution of Candida albicans in dental biofilm of Chinese children associated with severe early childhood caries. Arch. Oral Biol. 57(8), 1048–1053 (2012). 11 Klinke T, Guggenheim B, Klimm W,
Thurnheer T. Dental caries in rats associated with Candida albicans. Caries Res. 45(2), 100–106 (2011). 12 Falsetta ML, Klein MI, Colonne PM et al.
Symbiotic relationship between Streptococcus mutans and Candida albicans synergizes virulence of plaque biofilms in vivo. Infect. Immun. 82(5), 1968–1981 (2014). 13 Thein ZM, Seneviratne CJ, Samaranayake
YH, Samaranayake LP. Community lifestyle of Candida in mixed biofilms: a mini review. Mycoses 52(6), 467–475 (2009). 14 Xu H, Jenkinson HF, Dongari-Bagtzoglou A.
Innocent until proven guilty: mechanisms and roles of Streptococcus–Candida interactions in oral health and disease. Mol. Oral Microbiol. 29(3), 99–116 (2014).
influence of Streptococcus mutans on adhesion of Candida albicans to acrylic surfaces in vitro. Arch. Oral Biol. 34(5), 347–353 (1989). glucosyltransferase B in the interactions of Candida albicans with Streptococcus mutans and experimental pellicle formed on hydroxyapatite surface. Appl. Environ. Microbiol. 77(18), 6357–6367 (2011). 17 Pereira-Cenci T, Deng DM, Kraneveld EA
et al. The effect of Streptococcus mutans and Candida glabrata on Candida albicans biofilms formed on different surfaces. Arch. Oral Biol. 53(8), 755–764 (2008). 18 Metwalli KH, Khan SA, Krom BP et al.
Streptococcus mutans, Candida albicans, and the human mouth: a sticky situation. PLoS Pathog. 9, e1003616 (2013). 19 Sztajer H, Szafranski SP, Tomasch J et al.
Cross-feeding and interkingdom communication in dual-species biofilms of Streptococcus mutans and Candida albicans. ISME J. doi:10.1038ismej.73 (2014) (Epub ahead of print). 20 Peleg AY, Hogan DA, Mylonakis E.
Medically important bacterial–fungal interactions. Nat. Rev. Microbiol. 8(5), 340–349 (2010).
www.futuremedicine.com
1297
