Glycan Modulation of Inflammatory Responses

Project 1: Siglec Modulation of Inflammatory Responses

Sialic acids (Sias) at outer ends of vertebrate glycan chains are recognized by Siglecs (Siarecognizing Ig-like lectins) on myeloid cells (neutrophils, monocytes and macrophages). Our overall hypothesis is that the activatory and Arg-mutated versions of CD33-related Siglecs represent evolutionary adjustments of inflammatory responsiveness of myeloid cells, which also face microbes expressing Siacontaining surface polysaccharides that can subvert inhibitory Siglecs. Our studies address the significance of mammalian activatory and Arg-mutated Siglecs in modulating the baseline “set-state” of the myeloid cell innate immune response, as well as the inflammatory responses to bacterial pathogens bearing Sias.


Project 2: Microbial Glycan Mimicry and Glycosidases in Inflammatory Responses

This project examines the innate immune and inflammatory functions of myeloid cells (neutrophils and macrophages) upon challenge by infectious microbes that either (a) display glycans that mimic common host glycans or (b) produce glycosidases that can target (cleave) host glycoconjugates. This project focuses studies on the leading pathogens group A and B Streptococcus and Streptococcus pneumoniae (SPN). Deploying a unique suite of genetic tools, in which the host-pathogen equation is carefully manipulated in a controlled fashion from both sides, we will study infectious disease pathogenesis and innate immune responses in ex vivo and in vivo models of myeloid cell innate immune and inflammatory function.


Project 3: Genetic Analysis of Glycosaminoglycans in Inflammatory Responses

The objective is to study the function of the sulfated glycosaminoglycans (GAGs), heparan chondroitin and dermatan sulfate, in inflammation, with particular emphasis on sulfation of the chains on endothelial and myeloid cells. In this proposal, we plan to examine the impact of altering uronic acid 2-Osulfation and glucosamine 6-O-sulfation using mice with conditional alleles in these enzymes, and then extend this analysis to the major sulfated galactosaminoglycans: chondroitin-4-sulfate and dermatan sulfate. In the vasculature, chondroitins have been relegated to structural roles or as contributory factors to pathophysiological lipid deposition. However, other data suggest that both chondroitin and dermatan sulfate can participate in chemokine, growth factor, and morphogen action as well. These experiments will help establish roles of targeted genes in inflammation, which could validate new targets for treating chronic inflammation and edema caused by ischemia.


Project 4: Hyaluronan Catabolism in Inflammatory Responses

The main objective of this project is to better understand the role of Hyaluronan (HA) in tissue inflammatory responses. Our overall hypothesis is that HA is an important intermediate in control of inflammation, and our approach in testing this is by using tissue-specific expression of hyaluronidases to understand how HA functions in the system of innate immune recognition and defense. Catabolic fragments of HA can be recognized by Toll-like receptors (TLRs), MD2, and classical HA binding molecules such as CD44. Data suggests that inflammatory triggers such as injury and microbial products will initiate alternative outcomes dependent on the composition of extracelluar HA fragments. Our mouse genetic approach permits us to evaluate the in vivo consequences of HA catabolism in defined systems, and we study how HA influences the outcome of wound repair, allergy and infections.