Infectious Diseases & Biodefense at UVa

• Biodefense and infectious diseases in 2008 will move into the new Carter-Harrison 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 infect-ions. 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

0

50

100

150

200

250

300

350

400

µg/ml

CDC085

CDC520

EMU1

EMU7

EMU17

EMU32

EMU33

EMU56

MSA802

MSA803

MSA808

MSA812

CDC697

CDC698

MSA814

MSA815

Strain

MLCs of Metronidazole, Nitazoxanide and Tizoxanide: Aerobic Conditions

MetronidazoleNitazoxanideTizoxanide

IN VITRO ACTIVITY OF NITAZOXANIDE AGAINST METRONIDAZOLE-SENSITIVE AND RESISTANT TRICHOMONAS VAGINALIS

PFOR

Glucose

CoA

Acetyl -CoA

Pyruvate

CO 2

Fd or Fld(Reduced)

Fd or Fld(Oxidized)

Hydrogenase(H 2) or

Reductases(NADPH)

PFOR

Glucose

CoA

Acetyl -CoA

Pyruvate

CO 2

Fd or Fld(Reduced)

Fd or Fld(Oxidized)

Hydrogenase(H 2) or

Reductases(NADPH)

Nitazoxanide blocks pyruvate ferredoxin oxidoreductase by reversing pyruvate binding to thiamine pyrophosphate

Discovery strategy – Can we make second generation drugs based on knowledge of mode of action and importance of pKa?Paul Hoffman, Ph.D., UVA