Nizet Lab Research - New Research Directions

We are collaborating with the laboratory of Malak Kotb at the University of Tennessee-Memphis to study the specific roles of individual GAS superantigens in the pathogenesis of invasive streptococcal infection and toxic shock syndrome. Dr. Kotb and colleagues have recently discovered that specific human HLA Class II haplotypes are associated with high risk or protection from serious systemic disease. In an extension of these investigations, we are generating and testing specific GAS superantigen deletion mutants of clonal in human HLA specific macrophage lines and transgenic mice to determine the precise molecular interactions that precipate toxic shock syndrome and severe disease outcome. In companion experiments, we have observed that the cysteine protease SpeB of GAS serves to modulate the organism's superantigen expression profile and ability to trigger T-cell proliferation.

In Vivo Models of Early-Onset GBS Pneumonia and Septicemia
This collaborative research project is being developed with the laboratory of Dr. Gregory Heldt in the UCSD Division of Neonatology. We are using premature and full-term rabbits in a ventilated model of early onset GBS pneumonia, with bacterial challenge delivered intratracheally or intramniotically. Endpoints studied include pulmonary function and gas exchange, innate and cellular immune responses, and the function of the newborn pulmonary epithelium and endothelium as a barrier against systemic spread of infection. We are particularly interested in the role of the GBS ß-hemolysin/cytolysin exotoxin in lung injury and immune activation, and the ability of surfactant phospholipid to block the deleterious effects of the toxin. Histopathologic analysis is carried out with the assistance of Professor Kurt Benirschke of the UCSD Departments of Pathology and Reproductive Medicine.
Role of GAS Superantigens in Invasive Infection and Toxic Shock Syndrome
We are collaborating with the laboratory of Malak Kotb at the University of Tennessee-Memphis to study the specific roles of individual GAS superantigens in the pathogenesis of invasive streptococcal infection and toxic shock syndrome. Dr. Kotb and colleagues have recently discovered that specific human HLA Class II haplotypes are associated with high risk or protection from serious systemic disease. In an extension of these investigations, we are generating and testing specific GAS superantigen deletion mutants of clonal in human HLA specific macrophage lines and transgenic mice to determine the precise molecular interactions that precipate toxic shock syndrome and severe disease outcome. In companion experiments, we have observed that the cysteine protease SpeB of GAS serves to modulate the organism's superantigen expression profile and ability to trigger T-cell proliferation.
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< > Structure-function interactions of GAS surface M protein with host ligands (with P. Ghosh, UCSD) < > Aspects of IKK and JNK signaling in innate immunity (with T. Lawrence, Univ Hospital, London) < > A novel C. elegans model of anthrax pathogenesis and immunity (with R. Aroian, UCSD) < > GAS degradation of host chemokines in disease pathogenesis (with E. Hanski, Hebrew University) < > Discovery of novel antibiotics from marine natural products (with W. Fenical, Scripps Oceanography) < > Discovery of novel antibiotics from combinatorial chemical libraries (with A. Nefzi, Torrey Pines Institute) < > New aspects of hepcidin function in innate immunity and iron homeostasis (with R. Johnson, UCSD) < > GAS DNAse and escape from neutrophil extracellular NETs (with M. Kotb, U. Tennessee)
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