1. ITI 1 Immunity, Transplantation and INFECTION 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. Context:

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

3. ITI 3 1.1 Leading causes of death globally, 1999 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 12.7 9.9 7.1 4.8 4.2 4.0 3.0 1.9 Source: The World Health Report 2000, WHO Rank % of total N~55M

4. ITI 4 1.2 Leading causes of death in Africa, 1999 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 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 Rank % of total

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

6. ITI 6 2. Major new diseases have recently emerged.

7. ITI 7 2.1 Many “New” Infectious Agents/Diseases Have Been Identified Since 1975. 1976Cryptosporidium parvum (Cryptosporidiosis) 1976Legionella (Legionnaire’s Disease) 1976Ebola Virus (Ebola) 1982E. coli O157 (lethal food poisoning) 1982Borrelia burgdorferi (Lyme Disease) 1983HIV (AIDS) 1983Helicobacter pylori (peptic ulcers) 1989Hepatitis C (nonA-nonB Hepatitis) 1992Vibrio cholerae 0139 (new, virulent serotype of Cholera) 1993Four Corners/Sin Nombre Virus (Hantavirus Pulmonary Syndrome) 1995 Human Herpesvirus 8 (Kaposi’s Sarcoma) 1996 Prions (variant Creutzfeld-Jacob Disease = “Mad Cow” in humans) 1997H5N1 Influenza virus (Direct bird to human, super-virulent Flu) 1999 West Nile Virus (in N. America - Encephalitis) 2003SARS coronavirus (SARS)

8. ITI 8 2.2 HIV is Reversing Hard-Won Improvements in Life Expectancy in many African Countries. South-Africa 35 40 45 50 55 60 65 1950-551955-601960-651965-701970-751975-801980-851985-901990-951995-00 Life expectancy at birth, in years Botswana Uganda Zambia Zimbabwe Source: United Nations Population Division, 1998

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

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

13. ITI 13 4. New tools are in hand.

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

16. ITI 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. ITI 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. ITI 18 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. 7. Why Stanford?

19. ITI 19 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. And, finally, some examples of what’s happening now at Stanford.

20. ITI 20

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

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