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Publication

Synergism of Candida albicans and Staphylococcus aureus in an oral infection mouse model - Exploring underlying mechanisms and treatment options

Book - Dissertation

Oropharyngeal candidiasis, also referred to as "oral thrush", is a superficial infection of the oral cavity most often caused by the fungus Candida albicans. Considering that the human oral cavity is a densely colonized area harboring a tremendous number of microorganisms, C. albicans is in close interaction with other commensal species during infection. Synergistic interactions between these species can be associated with enhanced pathogenicity, altered infection outcomes and high mortality rates in animal models. Moreover, these infections are often accompanied with increased drug tolerance which makes their treatment very challenging. An infectious synergism is observed between the fungus C. albicans and the bacterium Staphylococcus aureus. Despite the recognized importance of S. aureus as a human pathogen, little attention has been paid to S. aureus as a component of the oral microbial flora. In 2015, a mouse model, referred to as oral-co-infection mouse model, was developed to study the pathogenic implications of oropharyngeal candidiasis when S. aureus is present. Research showed that mice suffering from oropharyngeal candidiasis, had a significantly higher oral colonization of S. aureus and were susceptible to a systemic S. aureus infection. However, S. aureus is not invasive itself and thus requires a portal of entry to cause systemic infections. Although there is no clear evidence, it is possible that in these cases, oropharyngeal candidiasis might be the underlying cause of the systemic bacterial infection.In the first objective of this study, we aimed to provide insights into the infectious synergism between C. albicans and S. aureus in the mouse model of oral infection. We identified C. albicans Als1 and Als3 adhesins as the molecular players involved in the interaction with S. aureus and in subsequent bacterial dissemination. Remarkably, we additionally identified the host phagocytic immune response as a key element required for bacterial dissemination. We found that the level of immunosuppression of the host plays a critical yet paradoxical role in this process. In addition, secretion of candidalysin, the C. albicans peptide responsible for host immune activation and cell damage, is required for C. albicans colonization and subsequent bacterial dissemination. Finally, we found that the physical interaction between C. albicans and S. aureus enhances bacterial uptake by phagocytic immune cells, thereby enabling an opportunity to disseminate.In the second objective of this study, we investigated two innovative strategies for the prevention of S. aureus colonization and dissemination. As these polymicrobial infections are more drug tolerant compared to their corresponding single species infections, the possibility to use conventional drugs is limited. Hence, novel treatment strategies to prevent or eradicate polymicrobial infections are urgently needed. First, we tested a novel endolysin derived from a bacteriophage which specifically targets S. aureus. We found that administration of this endolysin in the drinking water of animals significantly reduced oral S. aureuscolonization and prevented subsequent dissemination. Secondly, we examined the capability of an aggregation-inducing peptide, which targets the C. albicans Als3 adhesin, to inhibit the interaction with S. aureus. We found that this peptide indeed inhibits in vitro adhesion of S. aureus to C. albicans, but not in vivo. In the final objective of this study, we explored the use of non-invasive imaging methods to further elucidate the mechanism of infectious synergism between C. albicans and S. aureus in an in vivo context. Pre-clinical non-invasive imaging techniques are increasingly used in research because they have the potential to deliver dynamic information on individual animals in real time. First, we explored the use of bioluminescence imaging to detect the colonization and dissemination of S. aureus throughout the disease process on a whole-body level. Although we could clearly visualize oral colonization of S. aureus using bioluminescence imaging, we could not detect dissemination to the internal organs. Secondly, we have performed pilot experiments using intravital microscopy to validate our hypothesis on the mechanism of bacterial dissemination at a cellular resolution in the oral co-infection mouse model, however, further optimization is needed.In conclusion, this thesis provides new insights into the multifaceted mechanisms leading to S. aureusdissemination during oropharyngeal candidiasis and highlights the potential of an endolysin-based treatment strategy. Moreover, we have made progress in setting the stage towards non-invasive imaging to study C. albicans - S. aureus infections.
Publication year:2021
Accessibility:Open