Transcript Victor Nizet

Basic & Translational Research on Common
and Serious Human Infectious Diseases
Center for Immunity, Infection &
Inflammation
Pediatrics & SSPPS
Focus 1: Bacterial
Pathogenesis
Focus 2: Innate Immunity
Focus 3: Novel Infectious
Disease
Therapeutics &
Vaccines
Research Interests
Molecular pathogenesis of commong invasive bacterial pathogens:
Virulence factor discovery, infectious disease modeling, understanding immune evasion
GAS, 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 activation
Host glycan receptors (lectin) involved in pathogen recognition, immune regulation
Glycoprotein remodeling in the immunopathogenesis of sepsis, coagulopathies
Genetics and mechanism of action of bacterial toxins:
Strep and staph pore-forming toxins/hemolysins, immune-disrupting proteases
Anthrax 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 vaccine
Designer antibodies and drugs for passive immunotherapy of drug-resistant pathogens.
Core Expertise
Bacterial molecular genetics
Mutagenesis, cloning, virulence factor discovery, “Molecular Koch’s postulates”
Innate immune function analysis
Antimicrobial peptides, complement system, macrophage and neutrophil function,
receptor signaling, transcriptional regulation, autophagy, cell death, chemotaxis
Tissue culture, flow cytometry, cytokines, Westerns, immunofluorescence, apoptosis,
neutrophils extracellular traps (NETs), signaling, transcriptional analyses.
Small animal models of bacterial infection:
Past: Rats, rabbits, fish
Current: Mice including multiple KO strains
Sepsis, pneumonia, meningitis, skin infection, wound infection, UTI, foreign body
Collaborative: Fruit flies, Worms
Preclinical analysis of antibiotic activity:
MIC/MBC testing (classical) and in the context of innate immune components
Have hundreds of strains of all important contemporary MDR pathogens for testing.
Spectrum and potency, post-antibiotic effect, risk of resistance, animal challenge for PK/PD
Treatment in any of the animal models above
Collaborations with Biotechnology/Pharma Companies
Ongoing in the Laboratory
New: high-throughput screening for compounds that sensitize MDR Grambacteria to clearance by the host innate immune system. (Liquid handling
system 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
Repositioning prolyl-hydroxlase inhibitor drugs used in anemia/vascular
disease therapeutics to boost white blood cell killing of MDR bacteria.
Novel platform to recruit and activate neutrophils to the site of invasive
fungal and bacterial pathogens.
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
Some of our collaborative research at scientific
interfaces
Richard Gallo
Innate
Immunity
Michael
Karin
Cell
Signaling
Ajit Varki
Glycobiolog
y
Edmund
Capparelli
PK/PD
Jack Dixon
Pharmacolog
y
Pieter Dorrestein
Microbial Products
Chris Glass
Macrophage
s
Jeffrey Esko
Glycobiology
Partho Ghosh
Structure/Functi
on
Ethan Bier
Bacterial
Toxins
Emily Troemel
Baxterial Toxins
Brad Moore
Marine
Antibiotics