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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
Siddiqui, Shoib S; Springer, Stevan A; Verhagen, Andrea et al. (2017) The Alzheimer's disease-protective CD33 splice variant mediates adaptive loss of function via diversion to an intracellular pool. J Biol Chem 292:15312-15320
van Wijk, Xander M; Döhrmann, Simon; Hallström, Björn M et al. (2017) Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin ?2 as a Host Factor for Bacterial Invasion. MBio 8:
Dharmadhikari, Gitanjali; Stolz, Katharina; Hauke, Michael et al. (2017) Siglec-7 restores ?-cell function and survival and reduces inflammation in pancreatic islets from patients with diabetes. Sci Rep 7:45319
Schwarz, Flavio; Landig, Corinna S; Siddiqui, Shoib et al. (2017) Paired Siglec receptors generate opposite inflammatory responses to a human-specific pathogen. EMBO J 36:751-760
Siddiqui, Shoib; Schwarz, Flavio; Springer, Stevan et al. (2017) Studies on the Detection, Expression, Glycosylation, Dimerization, and Ligand Binding Properties of Mouse Siglec-E. J Biol Chem 292:1029-1037
Miles, L A; Baik, N; Lighvani, S et al. (2017) Deficiency of plasminogen receptor, Plg-RKT , causes defects in plasminogen binding and inflammatory macrophage recruitment in vivo. J Thromb Haemost 15:155-162
Liu, Lin; Prudden, Anthony R; Bosman, Gerlof P et al. (2017) Improved isolation and characterization procedure of sialylglycopeptide from egg yolk powder. Carbohydr Res 452:122-128
Patras, Kathryn A; Coady, Alison; Olson, Joshua et al. (2017) Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract. Immunol Cell Biol 95:960-965
Dhamale, Omkar P; Lawrence, Roger; Wiegmann, Elena M et al. (2017) Arylsulfatase K is the Lysosomal 2-Sulfoglucuronate Sulfatase. ACS Chem Biol 12:367-373
Lin, Ann E; Autran, Chloe A; Szyszka, Alexandra et al. (2017) Human milk oligosaccharides inhibit growth of group B Streptococcus. J Biol Chem 292:11243-11249

Showing the most recent 10 out of 86 publications