<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System
ABSTRACT Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfec...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-06-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00910-19 |
| _version_ | 1818822619412037632 |
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| author | Olivia A. Todd Paul L. Fidel Janette M. Harro Jamese J. Hilliard Christine Tkaczyk Bret R. Sellman Mairi C. Noverr Brian M. Peters |
| author_facet | Olivia A. Todd Paul L. Fidel Janette M. Harro Jamese J. Hilliard Christine Tkaczyk Bret R. Sellman Mairi C. Noverr Brian M. Peters |
| author_sort | Olivia A. Todd |
| collection | DOAJ |
| description | ABSTRACT Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfection with these pathogens results in synergistic lethality that is partially dependent on exacerbated prostaglandin signaling, while monomicrobial infection is nonlethal. Therefore, the objective of this study was to identify staphylococcal virulence determinants that drive lethal synergism during polymicrobial IAI. Using the toxigenic S. aureus strain JE2, we observed that coinfection with C. albicans led to a striking 80 to 100% mortality rate within 20 h postinoculation (p.i.) while monomicrobial infections were nonlethal. Use of a green fluorescent protein (GFP)-P3 promoter S. aureus reporter strain revealed enhanced activation of the staphylococcal agr quorum sensing system during in vitro polymicrobial versus monomicrobial growth. Analyses by quantitative real-time PCR (qPCR), Western blot, and toxin functional assays confirmed enhanced agr-associated gene transcription and increases in secreted alpha- and delta-toxins. C. albicans-mediated elevated toxin production and hemolytic activity were determined to be agrA dependent, and genetic knockout and complementation of hla identified alpha-toxin as the key staphylococcal virulence factor driving lethal synergism. Analysis of mono- and polymicrobial infections 8 h p.i. demonstrated equivalent bacterial burdens in the peritoneal cavity but significantly elevated levels of alpha-toxin (3-fold) and the eicosanoid prostaglandin E2 (PGE2) (4-fold) during coinfection. Importantly, prophylactic passive immunization using the monoclonal anti-alpha-toxin antibody MEDI4893* led to significantly improved survival rates compared to those following treatment with isotype control antibody. Collectively, these results define alpha-toxin as an essential virulence determinant during C. albicans-S. aureus IAI and describe a novel mechanism by which a human-pathogenic fungus can augment the virulence of a highly pathogenic bacterium in vivo. IMPORTANCE Relatively little is known about the complex interactions and signaling events that occur between microbes and even less so about how microbial “cross talk” shapes human health and disease. Candida albicans (a fungus) and Staphylococcus aureus (a bacterium) are formidable human nosocomial pathogens, causing severe morbidity and mortality. Moreover, they are frequently coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. In this work, we have shown that coinfection with C. albicans and S. aureus is highly lethal, leading to >80% mortality by day 1 postinfection, whereas monoinfection with C. albicans or S. aureus does not cause mortality. This infectious synergism is dependent on the expression of staphylococcal alpha-toxin, and secretion of this potent virulence factor is actually augmented by C. albicans via an agr-dependent mechanism. Moreover, prophylactic neutralization of alpha-toxin with a monoclonal antibody is sufficient to elicit protection during coinfection. Therefore, we have demonstrated that a pathogenic fungus can enhance virulence determinants of a bacterium in vivo with devastating consequences to the host. These results have important implications in the surveillance and treatment of polymicrobial disease and highlight the dynamic intersection of environment, pathogens, and host. |
| first_indexed | 2024-12-18T23:26:58Z |
| format | Article |
| id | doaj.art-d0e5a7c9eab44807889d9025e2da07de |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-18T23:26:58Z |
| publishDate | 2019-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d0e5a7c9eab44807889d9025e2da07de2022-12-21T20:47:45ZengAmerican Society for MicrobiologymBio2150-75112019-06-0110310.1128/mBio.00910-19<named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing SystemOlivia A. Todd0Paul L. Fidel1Janette M. Harro2Jamese J. Hilliard3Christine Tkaczyk4Bret R. Sellman5Mairi C. Noverr6Brian M. Peters7Integrated Program in Biomedical Sciences, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USADepartment of Oral Biology, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USADepartment of Microbial Pathogenesis, School of Dentistry, University of Maryland—Baltimore, Baltimore, Maryland, USADepartment of Microbial Sciences, AstraZeneca, Gaithersburg, Maryland, USADepartment of Microbial Sciences, AstraZeneca, Gaithersburg, Maryland, USADepartment of Microbial Sciences, AstraZeneca, Gaithersburg, Maryland, USADepartment of Oral Biology, School of Dentistry, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USADepartment of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USAABSTRACT Candida albicans and Staphylococcus aureus are among the most prevalent nosocomial pathogens that are responsible for severe morbidity and mortality, even with appropriate treatment. Using a murine model of polymicrobial intra-abdominal infection (IAI), we have previously shown that coinfection with these pathogens results in synergistic lethality that is partially dependent on exacerbated prostaglandin signaling, while monomicrobial infection is nonlethal. Therefore, the objective of this study was to identify staphylococcal virulence determinants that drive lethal synergism during polymicrobial IAI. Using the toxigenic S. aureus strain JE2, we observed that coinfection with C. albicans led to a striking 80 to 100% mortality rate within 20 h postinoculation (p.i.) while monomicrobial infections were nonlethal. Use of a green fluorescent protein (GFP)-P3 promoter S. aureus reporter strain revealed enhanced activation of the staphylococcal agr quorum sensing system during in vitro polymicrobial versus monomicrobial growth. Analyses by quantitative real-time PCR (qPCR), Western blot, and toxin functional assays confirmed enhanced agr-associated gene transcription and increases in secreted alpha- and delta-toxins. C. albicans-mediated elevated toxin production and hemolytic activity were determined to be agrA dependent, and genetic knockout and complementation of hla identified alpha-toxin as the key staphylococcal virulence factor driving lethal synergism. Analysis of mono- and polymicrobial infections 8 h p.i. demonstrated equivalent bacterial burdens in the peritoneal cavity but significantly elevated levels of alpha-toxin (3-fold) and the eicosanoid prostaglandin E2 (PGE2) (4-fold) during coinfection. Importantly, prophylactic passive immunization using the monoclonal anti-alpha-toxin antibody MEDI4893* led to significantly improved survival rates compared to those following treatment with isotype control antibody. Collectively, these results define alpha-toxin as an essential virulence determinant during C. albicans-S. aureus IAI and describe a novel mechanism by which a human-pathogenic fungus can augment the virulence of a highly pathogenic bacterium in vivo. IMPORTANCE Relatively little is known about the complex interactions and signaling events that occur between microbes and even less so about how microbial “cross talk” shapes human health and disease. Candida albicans (a fungus) and Staphylococcus aureus (a bacterium) are formidable human nosocomial pathogens, causing severe morbidity and mortality. Moreover, they are frequently coisolated from central venous catheters and deep-seated infections, including intra-abdominal sepsis. In this work, we have shown that coinfection with C. albicans and S. aureus is highly lethal, leading to >80% mortality by day 1 postinfection, whereas monoinfection with C. albicans or S. aureus does not cause mortality. This infectious synergism is dependent on the expression of staphylococcal alpha-toxin, and secretion of this potent virulence factor is actually augmented by C. albicans via an agr-dependent mechanism. Moreover, prophylactic neutralization of alpha-toxin with a monoclonal antibody is sufficient to elicit protection during coinfection. Therefore, we have demonstrated that a pathogenic fungus can enhance virulence determinants of a bacterium in vivo with devastating consequences to the host. These results have important implications in the surveillance and treatment of polymicrobial disease and highlight the dynamic intersection of environment, pathogens, and host.https://journals.asm.org/doi/10.1128/mBio.00910-19Candida albicansintraabdominal infectionpolymicrobial |
| spellingShingle | Olivia A. Todd Paul L. Fidel Janette M. Harro Jamese J. Hilliard Christine Tkaczyk Bret R. Sellman Mairi C. Noverr Brian M. Peters <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System mBio Candida albicans intraabdominal infection polymicrobial |
| title | <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System |
| title_full | <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System |
| title_fullStr | <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System |
| title_full_unstemmed | <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System |
| title_short | <named-content content-type="genus-species">Candida albicans</named-content> Augments <named-content content-type="genus-species">Staphylococcus aureus</named-content> Virulence by Engaging the Staphylococcal <italic toggle="yes">agr</italic> Quorum Sensing System |
| title_sort | named content content type genus species candida albicans named content augments named content content type genus species staphylococcus aureus named content virulence by engaging the staphylococcal italic toggle yes agr italic quorum sensing system |
| topic | Candida albicans intraabdominal infection polymicrobial |
| url | https://journals.asm.org/doi/10.1128/mBio.00910-19 |
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