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National Emerging Infectious Diseases Laboratories Institute NIH Blue Ribbon Panel March 13, 2008 Mark S Klempner, M.D. NEIDL Scientific Programs (examples) Antimicrobial resistance (e.g. MDR, XDR tuberculosis) Multivalent vaccines (e.g. hemorrhagic fever viruses/EEE)
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National Emerging Infectious Diseases Laboratories Institute NIH Blue Ribbon Panel March 13, 2008 Mark S Klempner, M.D. • NEIDL Scientific Programs (examples) • Antimicrobial resistance (e.g. MDR, XDR tuberculosis) • Multivalent vaccines (e.g. hemorrhagic fever viruses/EEE) • Acute Lung Injury Repair (e.g. influenza) • Vector transmitted disease interruption (e.g. dengue, hemorrhagic fever viruses) • NEIDL Support for Collaborative Research
Prevalence of Multi-drug Resistant (2 first line drugs) Tuberculosis Among New TB Cases (1994-2002)ANDCountries with Extensively Drug Resistant (XDR, 4 drugs) TB (1/ 2007)
1. Drug Network Inference 2. KO Off On 3. Gene 1 # of Cells Gene Expression 1 2 3 4 A Network Biology Approach to Antibiotic Action Synthetic Biology Systems Biology
Bactericidal Antibiotics: Stimulate Hydroxyl Radical Formation MA Kohanski et al., Cell 130,1-14, 2007
geneX,Y,Z null Genomics Platform for Studying Antibiotic Action Against Drug Resistant M. tuberculosis GROWTH ASSAY with sub-lethal dose of drug Essential for Growth High Value Targets Essential for Survival SURVIVAL ASSAY with lethal dose of drug
Multidrug resistant M. tuberculosis BSL-3 Extensively drug resistant M. tuberculosis BSL3/4
Avian Influenza (H5N1):Why are we concerned? • Poultry and migratory birds in many countries affected simultaneously • Highly pathogenic • High case fatality among • humans • Majority of human population lacks immunity • Co-circulating human & avian influenza viruses with risk of emergence of pandemic strain July,2006
The Normal Alveolus Type I Epithelial Cell Endothelium (vessel) Type II Alveolar Epithelial Cell Macrophage Blood cells
Inhalation Injury e.g. influenza
Influenza viruses BSL-2 Highly virulent H5 influenza strains BSL3/4
Approaches to Filovirus Vaccines • Inactivated antigens • Whole virion preparations • Liposomes • DNA • Virus-like particles • Replication-defective vectors • Vaccinia • VEEV replicons • Adenovirus • Replicating vectors • Vesicular stomatitis virus • Paramyxovirus
Marburg virus BSL-4 Ebola virus BSL-4
TakingaBiteOutofVector-TransmittedInfectiousDiseases Klempner MS, Unnasch TR, and Hu LT. N Engl J Med 2007;356:2567-2569
Infection of the niche is an effective strategy for Wolbachia spreading in nature Wolbachia germline Wolbachia at the stem cell niche Frydman et al, Nature 2006
West Nile Virus, Dengue and malaria have a long incubation period in their mosquito vector Only mature mosquitoes transmit diseases Brownstein et al, 2003
Elimination or even slight reductions of the mature vector population show dramatic decrease on disease transmission A naturally occurring strain of the bacteria Wolbachia severely reduces the insect’s lifespan Min and Benzer, PNAS 1977
Dengue,Chickungunya, etc. BSL-3 CCHF and other Hemorrhagic fever viruses BSL-4
National Emerging Infectious Diseases Laboratories March 13, 2008 Mark S Klempner, M.D. • NEIDL Scientific Programs (examples) • Antimicrobial resistance (e.g. MDR, XDR tuberculosis) • Multivalent vaccines (e.g. hemorrhagic fever viruses/EEE) • Acute Lung Injury Repair (e.g. influenza) • Vector transmitted disease interruption (e.g. dengue, hemorrhagic fever viruses) • NEIDL Organization to Support Research Collaboration
National Emerging Infectious Diseases Laboratories March 13, 2008 Mark S Klempner, M.D. • NEIDL Scientific Programs • NEIDL Organization to • Support Research Collaboration