Transcript Description of the Infectious Diseases & Biodefense program

Infectious Diseases &
Biodefense at UVa
• Biodefense and infectious diseases in
2008 will move into the new CarterHarrison Research Building
– 23,800 nsf of lab and support space
– 4375 nsf of biosafety
level three
(BSL3/animal BSL3)
Infectious Diseases &
Biodefense at UVa
• The 26 faculty in ID/BioD are
– 100% NIH supported (median annual direct costs
$648,000),
– interactive (65% co-published), and
– come from 7 Departments.
• Rich tradition of ID at UVA
Diseases Studied
• Virology: HIV/AIDS, Influenza, Respiratory
Syncytial Virus, Ebola, KSHV, Hepatitis C
• Bacteriology:E. coli (including EAgg, STEC),
anthrax, tularemia, legionella, pertussis, yersinia,
community-acquired MRSA, Ps. aeruginosa, H.
pylori, Salmonella
• Eukaryotes: Candida, Amebiasis, Cryptosporidiosis
Host Response
• Human innate and acquired immunity to enteric
infections, HIV, influenza
• Human genetic epidemiology of infectious
diseases
• Animal models (rodent and C. elegans) to study
host response to amebiasis, cryptosporidiosis,
hepatitis C, KSHV, influenza
International Health Aspects
• Bangladesh: child cohort being studied for
enteric and respiratory infections.
• Tanzania and Uganda: at KCMC studies of HIV,
TB, enteric infections. At Kampala
studies of sepsis
in HIV/AIDS
• Brazil & Haiti: impact of enterics on HIV
treatment and malnutrition
Biodefense
• Category A: Anthrax, Tularemia, Ebola,
Smallpox, Plague
• Category B: Food & waterborne pathogens
(amebiasis, cryptosporidiosis, giardiasis, E. coli,
salmonella), Burkholderia
• Category C: Influenza, rabies, antibiotic resistant
bacteria
Nitazoxanide: A Broad Spectrum Anti-bacterial
Anti-parasitic and Anti-viral Drug
• Romark Laboratories markets this drug as Alinia
• FDA approved for Cryptosporidium and Giardia
• USDA approved for Sarcocystis neurona
• Off label – Entamoeba, Trichomonas, helmiths
• Anaerobic bacteria – Clostridium, C. difficile, etc.
• Microaerobic bacteria – Helicobacter pylori, Campylobacter jejuni
• Viruses – active against Influenza A and B, Hepatitis C and
rotavirus, but not paraFlu
Anti-parasitic Drugs
IN VITRO ACTIVITY OF NITAZOXANIDE AGAINST
METRONIDAZOLE-SENSITIVE AND RESISTANT
TRICHOMONAS VAGINALIS
MLCs of Metronidazole, Nitaz oxanide and Tiz oxanide:
Aerobic Conditions
400
350
300
250
µg/ml 200
Metronidazole
Nitazoxanide
Tizoxanide
150
100
50
0
CDC CDC EMU EMU EMU EMU EMU EMU MSA MSA MSA MSA CDC CDC MSA MSA
085 520
1
7
17
32
33
56
802 803 808 812 697
698
814 815
Strain
Nitazoxanide blocks pyruvate ferredoxin oxidoreductase
by reversing pyruvate binding to thiamine pyrophosphate
Glucose
Pyruvate
CoA
Fd or Fld
(Reduced)
PFOR
CO 2
Fd or Fld
(Oxidized)
Hydrogenase
(H 2 ) or
Reductases
(NADPH)
Acetyl -CoA
Discovery strategy – Can we make second generation drugs
based on knowledge of mode of action and importance of pKa?
Paul Hoffman, Ph.D., UVA