Project 2 lead by Victor Nizet, M.D. complements the overall PEG in a unique fashion, by probing what happens when the glycobiological homeostasis ofthe mammalian host is perturbed by exogenous factors. Specifically, this project examines the innate immune and inflammatory functions of myeloid cells (neutrophils and macrophages) upon challenge by infecfious microbes that either (a) display glycans that mimic common host glycoconjugates or (b) produce glycosidases that can target (cleave) host glycoconjugates. Either phenotypic property has the potential to alter the glycobiologial homeostasis of the host and subvert normal myeloid cell signaling, innate immunity, and inflammatory responses. The project focuses upon three bacterial pathogens of great importance to human medicine, group A Streptococcus (GAS), group B Streptococcus (GBS) and Streptococcus pneumoniae (SPN). Our molecular genetic approach involves generation of precise, live isogenic bacterial reagents that differ only by the expression of a surface glycan or the deployment of a surface-associated or secreted glycosidases. Our PEG collaborators provide complementary expertise and reagents to measure changes in, or genetically alter, the corresponding glycan receptor molecules on host leukocytes or in the whole animal.
In Aims 1 and 2, we use GBS to determine how bacterial sialic acid (Sia) mimicry and SPN sialidase expression modulate CD33rSiglec- mediated myeloid cell innate immune and inflammatory responses, respecfively.
In Aims 3 and 4, we determine how GAS hyaluronic acid (HA) expression modulates and how GBS hyaluronidase expression modulates CD44-mediated myeloid cell innate immune and infiammatory responses Deploying this unique suite of tools, in which the host-pathogen equation is carefully manipulated in a controlled fashion from both sides, we will study infecfious disease pathogenesis and innate immune responses in ex vivo and in vivo models of myeloid cell innate immune and inflammatory funcfion.
Glycan (sugar) molecules decorate the surface of human cells and are involved in regulafing the functions of our white blood cells in immune defense and inflammation. Several bacterial pathogens either (a) decorate their own surfaces with sugar molecules mimicking the host or (b) produce enzymes that destroy such sugar molecules. This proposal we study how these properties contribute to disease or promote inflammation.
|Schommer, Nina N; Muto, Jun; Nizet, Victor et al. (2014) Hyaluronan breakdown contributes to immune defense against group A Streptococcus. J Biol Chem 289:26914-21|
|Lin, Ann E; Autran, Chloe A; Espanola, Sophia D et al. (2014) Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J Infect Dis 209:389-98|
|Mooij, H L; Cabrales, P; Bernelot Moens, S J et al. (2014) Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. J Am Heart Assoc 3:e001274|
|Padler-Karavani, Vered; Hurtado-Ziola, Nancy; Chang, Yung-Chi et al. (2014) Rapid evolution of binding specificities and expression patterns of inhibitory CD33-related Siglecs in primates. FASEB J 28:1280-93|
|Muto, Jun; Morioka, Yasuhide; Yamasaki, Kenshi et al. (2014) Hyaluronan digestion controls DC migration from the skin. J Clin Invest 124:1309-19|
|Xu, Ding; Esko, Jeffrey D (2014) Demystifying heparan sulfate-protein interactions. Annu Rev Biochem 83:129-57|
|Thacker, Bryan E; Xu, Ding; Lawrence, Roger et al. (2014) Heparan sulfate 3-O-sulfation: a rare modification in search of a function. Matrix Biol 35:60-72|
|Chang, Yung-Chi; Olson, Joshua; Beasley, Federico C et al. (2014) Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo. PLoS Pathog 10:e1003846|
|van Sorge, Nina M; Cole, Jason N; Kuipers, Kirsten et al. (2014) The classical lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe 15:729-40|
|Zhang, Bing; Xiao, Wenyuan; Qiu, Hong et al. (2014) Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J Clin Invest 124:209-21|
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