The human immune system employs several specific and non-specific defense mechanisms to recognize and respond to pathogens. The innate immunity is one of the first interactions of this system with microorganisms. The human body is also a host to a variety of microorganisms including bacteria and fungi which are commonly referred to as the human microbiome. It is known that conserved molecular constructs associated with microorganisms can trigger the innate immune response in the human body. Some of these Pathogen-Associated Molecular Patterns (PAMPs) consist of peptidoglycan (PG) motifs, derived from the bacterial cell wall. These fragments can be recognized by human immune receptors such as nucleotide-binding oligomerization domain (NOD) proteins. Interestingly, some of the yeast cells can also sense these PG fragments. While significant insights into the importance of these bacterial derived peptidoglycans have been provided in recent years, details about these recognition processes at molecular level is not yet completely known. Here, we studied Candida albicans, one of the most common fungal cells in the human microbiome, that undergoes a morphological transformation from a non-invasive budding yeast to an invasive hyphae form upon interaction with the peptidoglycan fragments. This process is mediated by the adenylyl cyclase, Cyr1. Structural similarities between Cyr1 protein and NOD proteins suggest that the PG fragments can directly bind to Cyr1 protein and initiate the pathogenic morphological transformation of C. albicans. To probe the role of the PG fragments in the invasive transformation of the C. albicans and to explore possible connections to human immune responses, a library of bacterial cell wall peptidoglycan analogues was chemically synthesized. The binding affinities for the synthesized ligands and target proteins are explored using a Surface Plasmon Resonance (SPR) assay. Moreover, the ability of these ligands to initiate morphological change in fungal cells as well as immune responses in human cells is investigated. Considering the importance of these immune sensing processes in several pathological conditions including inflammatory bowel disease (IBD), colon cancer and infection, we hope that our work will help to map out the biochemistry surrounding microbiome and PG fragments to tune the mechanism of innate immune regulation in diseases.

Bacterial derived peptidoglycans and their role in the regulation of immune responses in the human microbiome

2019 Spring National Meeting

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