Characterizing the Interaction between Bacterial Derived Carbohydrates and Cyr1 and Its Role in Hyphal Growth in Candida albicans

The human body hosts a variety of microorganisms including bacteria and fungi as a part of the human microbiome. Whether as a commensal or pathogenic interaction, the process in which these eukaryotic and prokaryotic cells sense the presence of each other and respond accordingly is a key aspect of understanding the biology of the human microbiome and immune system. A wide range of fungal cells are known to reside in different sites in the human body. Some of these cells, as opportunistic microorganisms, can be the cause of major health complications in immunocompromised patients. Recent studies have shown that specific fragments associated with microorganisms can be recognized by these fungi and cause morphological changes. Some of these Pathogens‐Associated Molecular Patterns (PAMPs) are known to be recognized by the human immune system as well and lead to further activation of immune responses. Understanding the role of these fragments interacting with fungal cells is crucial for studying the pathogenicity of these microorganisms. In this regard, we investigated the Candida albicans, the most common pathogenic fungus in humans. Going from a budding yeast morphology to an invasive hyphae form, C. albicans can invade epithelial cells and cause further infection. This transformation is mediated by the adenylyl cyclase, Cyr1, and different triggers, including bacterial cell wall fragments, have been suggested to activate the Cyr1 protein and induce the hyphal growth of the cells. Interestingly, a host of bacterial peptidoglycan fragments have been shown to be recognized by the human immune system as well and bind to nucleotide‐binding oligomerization domain‐like receptors, or NOD‐like receptors. Structural similarities between Cyr1 protein and NOD proteins suggest that these peptidoglycan fragments of the bacterial cell wall can directly bind to Cyr1 protein and initiate the downstream pathway causing pathogenic morphological transformation of C. albicans . In this study, a small library of bacterial derived carbohydrates, including chemically synthesized peptidoglycan derivatives alongside with anthracyclines produced by Streptomyces was prepared and tested for their ability to induce hyphal growth in C. albicans cells. The binding between these compounds and the leucine‐rich repeat (LRR) domain of Cyr1 protein was further investigated via Surface Plasmon Resonance assay. These results demonstrate that Cyr1 can bind to peptidoglycan derivatives of bacterial cell wall with high affinity and further activate the hyphal growth of the C. albicans. These findings can lead us to a more detailed investigation of the binding process at molecular level and to study the Cyr1 protein as a potential target for inhibition of C. albicans pathogenicity via small molecule inhibitors. Support or Funding Information The authors are thankful for support from the Delaware COBRE program, supported by a grant from the National Institute of General Medical Sciences (NIGMS 1 P30 GM110758 and 1 P20 GM104316‐01A1) from the National Institutes of Health. Acknowledgement is gratefully made to the National Science Foundation (CAREER CHE 1554967) for support of this research. We thank Daniel Scanlon, James Melnyk, Amy Schaefer, Kristen DeMeester for their support. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .