Candida species are considered to be one of the leading causes of nosocomial acquired infections within critical care units, as well as afflicting immune suppressed individuals such as HIV positive patients. Candida utilizes a variety of virulence factors for colonization and infection of the host. Candida species are opportunistic fungi, which normally do not cause infection in healthy individuals. Oftentimes, infection with Candida in the critical care ward is associated with antimicrobial treatment of a current bacterial infection. This presentation of Candida is likely due to inadvertent killing of the normal flora in the body allowing for growth of the fungus. Polymicrobial infections involving C. albicans affect almost 27% of patients. It has recently been demonstrated that C. albicans and bacteria can affect each other's biological activities through the recognition of quorum sensing molecules secreted by both the bacteria and C. albicans. The primary hypothesis of this study is that Candida albicans harbors several genetic determinants that allow it to sense and respond to the majority of bacterial species with which it interact within the host environment. In this study we will investigate ten genes from C. albicans that play a role in Candida-bacterial interactions we identified from previous screen of a mutant library of 18,000 C. albicans strains for the ability t filament in the presence of select bacteria. As these genetic mutants were identified by co-cultivation in the presence of bacteria, we have also chosen to test the candidate strains against a panel of known bacterial secreted molecules in order to categorize the appropriate response pathway. We will also determine the temporal expression of the selected genes when Candida is exposed to bacteria. Mutant strains will be grown in the presence or absence of bacteria to determine if gene expression is constitutive or induced by the presence of bacteria. We will also ascertain the virulence attributes of these selected strains using an invertebrate infection model. The short term benefits from this study will help in providing a basic understanding of the process by which Candida interacts with various bacterial species. Understanding what genetic determinants are important for Candida-bacterial interactions will be useful for exploiting novel bacterial molecules for antifungal development. Under many conditions for identifying new antifungal or antibiotic compounds, scientists tend to explore the environments of the soil and water and other ecological niches for new compounds, but have not looked at the microbes within the human body. In our case with the current interest in the human microbiome and how its organization affects human health, this could open a new door for novel compounds that could directly target C. albicans growth without disrupting other microflora that are necessary for maintaining homeostasis with the human host. In the long-term, there is the potential for development of novel antimicrobial agents that could be used either alone or in combination with current therapies for treatment of fungal infections.
Candida albicans is the fourth most common infectious organism isolated from critically ill patients, and finding a way to curtail C. albicans growth in patients can often be frustrating as most antifungals are fungistatic and depend on the host's immune system to clear an infection. The purpose of this project is to examine several genes that have been identified to play a role in the cross-species communication of C. albicans with various bacteria. Understanding the genetics behind these interactions has the potential for developing new insight into how we can control C. albicans growth in immunocompromised patients, and assess the potential in utilizing bacterial molecules as novel antifungal agents that could lessen the impact of C. albicans on patient mortality.
| Graus, Matthew S; Wester, Michael J; Lowman, Douglas W et al. (2018) Mannan Molecular Substructures Control Nanoscale Glucan Exposure in Candida. Cell Rep 24:2432-2442.e5 |
