The interactions that occur between microbes within the human body are central to both human health and disease. For example, the synergy between organisms within the normal microflora provides an important protective barrier against potential pathogens. At the same time, many illnesses, such as respiratory infections, gastroenteritis, and periodontal diseases, often involve multiple microorganisms. The study of microbe-microbe interactions is essential for an understanding of the in vivo activities of both commensal and pathogenic microorganisms.

Recent research illustrates that many of the interactions between microbes involve factors that are also important an organism's ability to cause disease in humans. Thus, we can also use microbe-microbe interaction systems to better understand the molecular mechanisms that underlie different aspects of the host-pathogen relationship.

Interactions between Pseudomonas aeruginosa and Candida albicans

Pseudomonas aeruginosa is both a common environmental bacterium and an important opportunistic pathogen that is capable of causing a variety of severe infections. This bacterium can cause particularly devastating infections in the lungs of individuals with certain predisposing conditions such as Cystic Fibrosis. P. aeruginosa virulence is due to many factors including its production of a wide array of secreted virulence determinants, its formation of persistent biofilms, and its high levels of resistance to many antibiotics. P. aeruginosa is often found in mixed infections with other opportunistic pathogens such as the dimorphic fungus Candida albicans. Both clinical data and in vitro studies indicate that P. aeruginosa is antagonistic towards C. albicans. Their physical interactions in vitro are illustrated in Fig. 1.

Fig. 1 P. aeruginosa attaches to (left), forms biofilms on (right), and kills C. albicans filaments. Functional type IV pili and hemolytic phospholipase C contribute to the killing of fungal cells.

We are currently focused on (i) understanding the bacterial and fungal factors involved in initial attachment, (ii) the regulation of bacterial virulence upon association with a eukaryotic cell surface, and (iii) the mechanism by which P. aeruginosa virulence determinants contribute to fungal killing. In collaboration with the other labs at Dartmouth that focus on research relating to Cystic Fibrosis, we are investigating the similarities and differences between P. aeruginosa virulence towards fungi and P. aeruginosa virulence towards airway epithelial cells. This will allow us to better exploit our microbial model system.

Effects on Candida albicans morphology

The presence of P. aeruginosa causes C. albicans to grow as yeast despite conditions that would normally promote hyphae formation. Using a genetic screen to identify mutants unable to influence C. albicans morphology, we found that the P. aeruginosa 3-oxo-C12-homoserine lactone quorum sensing molecule, which is produced at high concentrations in dense cultures and in biofilms, affects C. albicans morphology (Fig. 2). We are now in the process of characterizing the mechanism by which this molecule interferes with the C. albicans morphology-related signaling cascades.

Fig. 2 C. albicans in the control cultures (left) and in the presence P. aeruginosa 3OC12HSL (right).

C. albicans morphological transitions are essential to its success as an invasive pathogen. Because there is ample evidence suggesting that our normal microbial flora protects us against fungal pathogens, we are interested in identifying secreted molecules produced by normal flora organisms that similarly impact C. albicans growth and hyphae formation.