center for immunity, infection & inflammation pediatrics & sspps focus 1: bacterial...
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Center for Immunity, Infection & Inflammation
Pediatrics & SSPPS
Focus 1: Bacterial Pathogenesis
Focus 2: Innate Immunity
Focus 3: Novel Infectious Disease Therapeutics & Vaccines
Basic & Translational Research on Commonand Serious Human Infectious Diseases
Research InterestsMolecular pathogenesis of commong invasive bacterial pathogens:
Virulence factor discovery, infectious disease modeling, understanding immune evasionGAS, GBS, MRSA, Pneumococcus, Anthrax, MDR Gram- Pathogens
Understanding basic functions of the innate immune system: Antimicrobial peptides, complement system, macrophage and neutrophil function,receptor signaling, transcriptional regulation, autophagy, cell death, chemotaxis
Glycobiology of the host-pathogen interface:Molecular mimicry by bacterial glycans (sialic acid, hyaluronic acid)Bacterial glycosidases in inflammatory activationHost glycan receptors (lectin) involved in pathogen recognition, immune regulationGlycoprotein remodeling in the immunopathogenesis of sepsis, coagulopathies
Genetics and mechanism of action of bacterial toxins:Strep and staph pore-forming toxins/hemolysins, immune-disrupting proteasesAnthrax toxins, cholera toxin, how they disrupt host barrier function
Novel approaches to treat multi-drug resistant bacterial infections:Virulence factor inhibitors (disarm rather than kill the pathogen)Drugs that boost the killing activity of phagocytic cells (neutrophils/macrophages)Studying how antibiotics synergize with the innate immune system
Passive and active vaccination strategies for challenging pathogens:Novel approach to safe and universal GAS vaccineDesigner antibodies and drugs for passive immunotherapy of drug-resistant pathogens.
Core Expertise
Bacterial molecular geneticsMutagenesis, cloning, virulence factor discovery, “Molecular Koch’s postulates”
Innate immune function analysisAntimicrobial peptides, complement system, macrophage and neutrophil function,receptor signaling, transcriptional regulation, autophagy, cell death, chemotaxisTissue culture, flow cytometry, cytokines, Westerns, immunofluorescence, apoptosis,neutrophils extracellular traps (NETs), signaling, transcriptional analyses.
Small animal models of bacterial infection:Past: Rats, rabbits, fishCurrent: Mice including multiple KO strains
Sepsis, pneumonia, meningitis, skin infection, wound infection, UTI, foreign bodyCollaborative: Fruit flies, Worms
Preclinical analysis of antibiotic activity:MIC/MBC testing (classical) and in the context of innate immune componentsHave hundreds of strains of all important contemporary MDR pathogens for testing.Spectrum and potency, post-antibiotic effect, risk of resistance, animal challenge for PK/PDTreatment in any of the animal models above
Collaborations with Biotechnology/Pharma Companies Ongoing in the Laboratory
Fit-for-function biotherapeutics (single and multidomain antibodies) that optimally interface with the biology of each target antigen (MDR bacteria), to focus immune activation and mediate enhanced signaling
Novel platform to recruit and activate neutrophils to the site of invasive fungal and bacterial pathogens.
Repositioning prolyl-hydroxlase inhibitor drugs used in anemia/vascular disease therapeutics to boost white blood cell killing of MDR bacteria.
New: high-throughput screening for compounds that sensitize MDR Gram-bacteria to clearance by the host innate immune system. (Liquid handlingsystem being delivered this month for 384/96 well plate screens)
Collaboration with Kary Mullis to redirect pre-existing antibodies we all possess to target MDR bacterial pathogens
Some of our collaborative research at scientific interfaces
Ethan Bier Bacterial Toxins
Richard GalloInnate Immunity
Ajit VarkiGlycobiolo
gy
Jack DixonPharmacolo
gy
Pieter DorresteinMicrobial Products
Chris Glass
Macrophages
Jeffrey EskoGlycobiology
Edmund Capparelli
PK/PD
Partho GhoshStructure/Function
Brad MooreMarine
Antibiotics
Emily TroemelBaxterial Toxins
Michael KarinCell
Signaling