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.
|Patras, Kathryn A; Nizet, Victor (2018) Group B Streptococcal Maternal Colonization and Neonatal Disease: Molecular Mechanisms and Preventative Approaches. Front Pediatr 6:27|
|Raitman, Irene; Huang, Mia L; Williams, Selwyn A et al. (2018) Heparin-fibronectin interactions in the development of extracellular matrix insolubility. Matrix Biol 67:107-122|
|Dokoshi, Tatsuya; Zhang, Ling-Juan; Nakatsuji, Teruaki et al. (2018) Hyaluronidase inhibits reactive adipogenesis and inflammation of colon and skin. JCI Insight 3:|
|Miles, L A; Baik, N; Bai, H et al. (2018) The plasminogen receptor, Plg-RKT, is essential for mammary lobuloalveolar development and lactation. J Thromb Haemost 16:919-932|
|Qiu, Hong; Shi, Songshan; Yue, Jingwen et al. (2018) A mutant-cell library for systematic analysis of heparan sulfate structure-function relationships. Nat Methods 15:889-899|
|Godula, Kamil (2018) Following sugar patterns in search of galectin function. Proc Natl Acad Sci U S A 115:2548-2550|
|Huang, Mia L; Michalak, Austen L; Fisher, Christopher J et al. (2018) Small Molecule Antagonist of Cell Surface Glycosaminoglycans Restricts Mouse Embryonic Stem Cells in a Pluripotent State. Stem Cells 36:45-54|
|Huang, Mia L; Tota, Ember M; Verespy 3rd, Stephen et al. (2018) Glycocalyx Scaffolding to Control Cell Surface Glycan Displays. Curr Protoc Chem Biol 10:e40|
|Ge, Xiao Na; Bastan, Idil; Ha, Sung Gil et al. (2018) Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes. Exp Lung Res 44:98-112|
|Gordts, Philip L S M; Esko, Jeffrey D (2018) The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis. Matrix Biol 71-72:262-282|
Showing the most recent 10 out of 110 publications