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ITI
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.
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1. Infectious disease are directly responsible
for a major fraction of global mortality.
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1.1 Leading causes of death globally, 1999
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Rank
% of total
•
1
Ischaemic heart disease
12.7
•
2
Cerebrovascular disease
9.9
•
3
Acute lower respiratory infections
7.1
•
4
HIV/AIDS
4.8
•
5
Chronic obstructive pulmonary disease
4.8
•
6
Perinatal conditions
4.2
•
7
Diarrhoeal diseases
4.0
•
8
Tuberculosis
3.0
•
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Malaria
1.9
N~55M
Source: The World Health Report 2000, WHO
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1.2 Leading causes of death in Africa, 1999
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Rank
% of total
•
1
HIV/AIDS
20.6
•
2
Acute lower respiratory infections
10.3
•
3
Malaria
9.1
•
4
Diarrhoeal diseases
7.3
•
5
Perinatal conditions
5.9
•
6
Measles
4.9
•
7
Tuberculosis
3.4
•
8
Cerebrovascular disease
3.2
•
9
Ischaemic heart disease
3.0
•
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Maternal conditions
2.4
Source: The World Health Report 2000, WHO
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1.3 Infectious diseases are responsible for a
majority of deaths in children, worldwide.
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2. Major new diseases have recently emerged.
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1976
1976
1976
1982
1982
1983
1983
1989
1992
1993
1995
1996
1997
1999
2003
2.1 Many “New” Infectious Agents/Diseases
Have Been Identified Since 1975.
Cryptosporidium parvum (Cryptosporidiosis)
Legionella (Legionnaire’s Disease)
Ebola Virus (Ebola)
E. coli O157 (lethal food poisoning)
Borrelia burgdorferi (Lyme Disease)
HIV (AIDS)
Helicobacter pylori (peptic ulcers)
Hepatitis C (nonA-nonB Hepatitis)
Vibrio cholerae 0139 (new, virulent serotype of Cholera)
Four Corners/Sin Nombre Virus (Hantavirus Pulmonary Syndrome)
Human Herpesvirus 8 (Kaposi’s Sarcoma)
Prions (variant Creutzfeld-Jacob Disease = “Mad Cow” in humans)
H5N1 Influenza virus (Direct bird to human, super-virulent Flu)
West Nile Virus (in N. America - Encephalitis)
SARS coronavirus (SARS)
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2.2 HIV is Reversing Hard-Won Improvements in Life
Expectancy in many African Countries.
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65
60
Botswana
Uganda
South-Africa
55
Zambia
50
Zimbabwe
45
40
35
1950-55 1955-601960-651965-701970-751975-801980-851985-901990-951995-00
Source: United Nations Population Division, 1998
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3. Microbes now clearly implicated in the
etiology of many chronic diseases.
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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.
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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.
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3.3 Microbes and Autoimmunity.
Microbes may be triggers of an immune response
to “self”.
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4. New tools are in hand.
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4.1 New tools (many developed here):
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•‘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.
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5. We have a new understanding of hostpathogen systems.
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5.1 Microbial ecology in and out of the host.
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•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.
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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?
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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.
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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.
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New infections with HIV in 2003.
Total: 4.2 - 5.8M
30-40k
180-280k
36-54k
43-67k
Slide 2
150-270k
610-1100k
120-180k
3000-3400k
0.7-1k
Source: WHO
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100%
90%
Risk of dying of AIDS
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Lifetime risk of AIDS death for 15-year-old boys
in selected countries
Botswana
80%
Zimbabwe
70%
60%
50%
Côte d’Ivoire
Cambodia
Burkina
20% Faso
10%
0%
Zimbabwe
South Africa
Zambia
Kenya
40%
30%
Botswana
South Africa
Zambia
0%
risk halved over next 15 years
current level of risk maintained
Kenya
Côte d’Ivoire
Cambodia
Burkina Faso
5%
10%
15%
20%
25%
30%
35%
40%
Current adult HIV prevalence rate
Source: Zaba B, 2000 (unpublished data)
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