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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107150-03
Application #
8477260
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$247,625
Indirect Cost
$87,867
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping et al. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 126:2855-66
Varki, Ajit (2016) Biological Roles of Glycans. Glycobiology :
Yamaguchi, Masaya; Hirose, Yujiro; Nakata, Masanobu et al. (2016) Evolutionary inactivation of a sialidase in group B Streptococcus. Sci Rep 6:28852
Secundino, Ismael; Lizcano, Anel; Roupé, K Markus et al. (2016) Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation. J Mol Med (Berl) 94:219-33
Thacker, Bryan E; Seamen, Emylie; Lawrence, Roger et al. (2016) Expanding the 3-O-Sulfate Proteome--Enhanced Binding of Neuropilin-1 to 3-O-Sulfated Heparan Sulfate Modulates Its Activity. ACS Chem Biol 11:971-80
Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30
Schwarz, Flavio; Springer, Stevan A; Altheide, Tasha K et al. (2016) Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline. Proc Natl Acad Sci U S A 113:74-9
Sato, Emi; Muto, Jun; Zhang, Ling-Juan et al. (2016) The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation. J Invest Dermatol 136:1449-59
Miles, L A; Baik, N; Lighvani, S et al. (2016) Deficiency of Plasminogen Receptor, Plg-RKT, Causes Defects in Plasminogen Binding and Inflammatory Macrophage Recruitment in vivo. J Thromb Haemost :
Zaiss, Anne K; Foley, Erin M; Lawrence, Roger et al. (2016) Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo. J Virol 90:412-20

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