Immunity, Transplantation and INFECTION

1. Immunity, Transplantation and INFECTION Context: • Infectious disease are directly responsible for a major fraction of global mortality. • Microbes now clearly implicated in the etiology of many other, chronic diseases, as well. • Major new diseases have recently emerged. • Infectious diseases looming as biological weapons. • New tools are in hand. • New understanding of host-pathogen systems. • Stanford and the U.S. have a responsibility to build partnerships with developing countries.

2. 1. Infectious disease are directly responsible for a major fraction of global mortality.

3. 1 Ischaemic heart disease 2 Cerebrovascular disease 3 Acute lower respiratory infections 4 HIV/AIDS 5 Chronic obstructive pulmonary disease 6 Perinatal conditions 7 Diarrhoeal diseases 8 Tuberculosis 11 Malaria 1.1 Leading causes of death globally, 1999 Rank % of total 12.7 9.9 7.1 4.8 4.8 4.2 4.0 3.0 1.9 N~55M Source: The World Health Report 2000, WHO

4. 1 HIV/AIDS 2 Acute lower respiratory infections 3 Malaria 4 Diarrhoeal diseases 5 Perinatal conditions 6 Measles 7 Tuberculosis 8 Cerebrovascular disease 9 Ischaemic heart disease 10 Maternal conditions 1.2 Leading causes of death in Africa, 1999 Rank % of total 20.6 10.3 9.1 7.3 5.9 4.9 3.4 3.2 3.0 2.4 Source: The World Health Report 2000, WHO

5. 1.3 Infectious diseases are responsible for a majority of deaths in children, worldwide.

6. 2. Major new diseases have recently emerged.

7. 1976 Cryptosporidium parvum (Cryptosporidiosis) 1976 Legionella (Legionnaire’s Disease) 1976 Ebola Virus (Ebola) 1982 E. coli O157 (lethal food poisoning) 1982 Borrelia burgdorferi (Lyme Disease) 1983 HIV (AIDS) 1983 Helicobacter pylori (peptic ulcers) 1989 Hepatitis C (nonA-nonB Hepatitis) 1992 Vibrio cholerae 0139 (new, virulent serotype of Cholera) 1993 Four Corners/Sin Nombre Virus (Hantavirus Pulmonary Syndrome) 1995 Human Herpesvirus 8 (Kaposi’s Sarcoma) 1996 Prions (variant Creutzfeld-Jacob Disease = “Mad Cow” in humans) 1997 H5N1 Influenza virus (Direct bird to human, super-virulent Flu) West Nile Virus (in N. America - Encephalitis) 2003 SARS coronavirus (SARS) 2.1 Many “New” Infectious Agents/Diseases Have Been Identified Since 1975.

8. 2.2 HIV is Reversing Hard-Won Improvements in Life Expectancy in many African Countries. 65 60 Botswana Uganda 55 South-Africa Life expectancy at birth, in years Zambia 50 Zimbabwe 45 40 35 1950-55 1955-60 1960-65 1965-70 1970-75 1975-80 1980-85 1985-90 1990-95 1995-00 Source: United Nations Population Division, 1998

9. 3. Microbes now clearly implicated in the etiology of many chronic diseases.

10. 3.1 Microbes and Cancer. • Human papilloma virus and cervical carcinoma. • Hepatitis B and C viruses and hepatocellular carcinoma. • Helicobacter and gastric cancer. • Schistosoma and bladder cancer.

11. 3.2 Microbes and Allergy. Hygiene hypothesis (“idle hands are the devil’s plaything”): elimination of certain infections leads to inappropriate immune response to environmental materials.

12. 3.3 Microbes and Autoimmunity. Microbes may be triggers of an immune response to “self”.

13. 4. New tools are in hand.

14. 4.1 New tools (many developed here): • ‘omics of the pathogens, vectors and hosts. • Methods for engineering each. • HUGE increase in our understanding of the immune system and pathogen systems. • High throughput methods for analysis of host and pathogen. • Major developments in imaging.

15. 5. We have a new understanding of host-pathogen systems.

16. 5.1 Microbial ecology in and out of the host. • We are hosts for a diverse community of microbes. • More microbial cells than human cells in humans. • More microbial genes than human genes in humans. • Much crucial metabolism occurs in the microbes. • Natural keep “unnatural” at bay. • Environmental changes create new opportunities for infection.

17. 6. Questions to be addressed on the Infection side of ITI: • What factors lead to the emergence of new infectious diseases in humans? • How do microbial infections lead to chronic disease? • How does the interplay of complex microbial populations contribute to this? • What is the interplay of host and microbial genetics? • How can immunity be down-modulated to accept a transplanted organ but not infection? • How can vaccines and immune therapy be made more effective; e.g., for complex diseases? • How can immunity be stimulated in the very young or old?

18. 7. Why Stanford? • Many world leaders in component areas. • Many more studying diseases with infectious etiologies. • A Vaccine Center has already been established. • Stanford is a major power in genetics, ‘omics, imaging, immune monitoring, etc.

19. And, finally, some examples of what’s happening now at Stanford. • Development of novel vaccines in and for developing countries (e.g., rotavirus); Harry Greenberg, Gastroenterology. • Helicobacter and its association with gastric (up) and esophageal (down) cancer. Julie Parsonnet, Infectious Diseases and Stanley Falkow, Microbiology and Immunology. • Cytomegalovirus association with cardiovascular disease; Ed Mocarski, Microbiology and Immunology, Hannah Valantine & John Cooke, Medicine and Dave Lewis, Pediatrics. • Development of model host-pathogen systems; Man Wah Tan, Genetics and Brendan Bohannan, Biological Sciences. • Infection signatures (including smallpox); David Relman, Infectious Diseases and Pat Brown, Biochemistry. • Molecular mimicry of immune modulators by pathogens (e.g., viral IL6). Chris Garcia, Microbiology and Immunology.

21. 30-40k 36-54k 180-280k 150-270k 43-67k 610-1100k Slide 2 Slide 2 Slide 2 120-180k 3000-3400k 0.7-1k New infections with HIV in 2003. Total: 4.2 - 5.8M Source: WHO

22. Lifetime risk of AIDS death for 15-year-old boys in selected countries 100% 90% Botswana 80% Zimbabwe 70% Botswana South Africa Risk of dying of AIDS Zambia 60% Zimbabwe 50% Kenya South Africa risk halved over next 15 years Zambia Côte d’Ivoire 40% current level of risk maintained Cambodia Kenya 30% Côte d’Ivoire Burkina Faso 20% Cambodia Burkina Faso 10% 0% 0% 5% 10% 15% 20% 25% 30% 35% 40% Current adult HIV prevalence rate Source: Zaba B, 2000 (unpublished data)