Download Evolutionary History of the Human

Evolutionary History of the Human-Microbe Relationship
David A. Relman, MD
Evolutionary History of the Human-Microbe
Relationship
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History and types of host-microbe relationships
Human indigenous microbiota
What makes a microbe a pathogen?
Homo sapiens
RR1
Eukaryotes
Microbes
Homo sapiens
RR1
Eukaryotes
1.5 billion years of prokaryoteeukaryote encounters, prior to the
existence of humans!
Evolution of Parasitism
Accidental contact
Adaptation/benefit
Passive intracellular uptake
Adaptation/benefit
Establish niche
Induced uptake
Host response vs
microbial evasion
Symbiosis
Dependence
Human Indigenous Microbiota
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Humans are “sterile” (culture-negative) until rupture of
amniotic membranes
Transitions in gut microbiota: breast-fed, bottle-fed; then
diet, gender, age, antibiotics
Total microbiota: ≈1014 (human cells: ≈1013!)
Skin: ≈104-6 per gram (arm vs axilla); mouth: ≈1010-11 per
gram; stomach: ≈104 per gram; small intestine: ≈105-8 per
gram; colon: ≈1011-12 per gram
Human Indigenous Microbiota: Benefits?
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Vitamin production
Food degradation
Colonization resistance
Terminal differentiation of mucosa
“Education” of innate immune defenses
Promotes epithelial “homeostasis” in gut
Regulates energy extraction from food (obesity)
Mazmanian SK, et al. Cell. 2005;122:107-118; Rakoff-Nahoum S, et al. Cell. 2004;118:229-241; Backhed F, et al. Proc
Natl Acad Sci U S A. 2004;101:15718-15723.
Recognition of Commensal Microflora
by Toll-Like Receptors Is Required for
Intestinal Homeostasis
Rakaff-Nahoum S, et al. Cell. 2004;118:229-241.
Copyright ©2004 by Cell Press.
Bacteria
The Tree of Life
(based on rRNA sequences)
Archaea
Eukarya
Pace NR. Science. 1997;276:734-740.
Bacteria
Human-associated
Archaea
Eukarya
Pace NR. Science. 1997;276:734-740.
Bacteria
Modified from Handelsman J.
Microbiol Mol Biol Rev. 2004;68:669-685.
Bacteria
Modified from Handelsman J.
Microbiol Mol Biol Rev. 2004;68:669-685.
TM7 Abundance in Health and Disease
Average Percentage TM7 rDNA
(of total bacterial rDNA)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Healthy
Gingivitis
Mild
Moderate
Severe
Periodon- Periodon- Periodontitis
titis
titis
Brinig MM, et al. Appl Environ Microbiol. 2003;69:1687-1694.
Tongue
TM7 in the Human Mouth
TM7
IO25
IO25 filaments
Disease – 21.0 ± 2.2 μm
Health – 5.0 ± 1.0 μm
Ouverney CC, et al. Appl Environ Microbiol. 2003;69:6294-6298.
We are born ~100%
human, but die >90%
bacterial…
What are the features
of early microbial
colonization in the
human body?
16S rDNA Oligonucleotide Microarray
Pat Brown
Mike Eisen
Chana Palmer
Elies Bik
Microarray vs Clone Library Sequencing
ARRAY
SEQUENCE
ARRAY
SEQUENCE
C = Cecum
T = Transverse colon
S = Stool
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SPECIES
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GENUS
*
FAMILY
CLASS
PHYLUM
Palmer C, et al. Nucl Acids Res. 2006;34:e5
Colonization of the
Newborn Intestinal Tract
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Extreme early temporal variability, reflects
accidental exposures
No one “healthy pattern” in early days
Temporary equilibria frequently observed
Despite diverse, idiosyncratic profiles in first 6
months, communities progressively converged
toward a “generic” adult profile, becoming
increasingly similar to one another
Beauty Is More Than Skin Deep
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Brugia malayi and other filariae
are colonized by endosymbiotic
bacteria: Wolbachia spp.
Elimination of these bacteria
renders the filariae nonviable
and sterile!
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Filariasis patients treated
with doxycycline have fewer
bacteria within filariae, fewer
filarial embryos and more
filarial degeneration
Hoerauf A, et al. Lancet. 2001;357:1415-1416.
Clinical Infectious Diseases
2006; 42:1081-1089
Microfilariae levels
were significantly lower
in the doxycycline
group. Severity of
adverse reactions to
standard Rx was lower
in doxycycline group.
What Is a Pathogen?
Defining pathogenicity...
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Pathogens are those microbes that cause
damage to the host as part of their strategy for
multiplication within, or transmission to or from
the host
Pathogens may make use of privileged sites
within the host
Not all infections caused by a pathogen are
symptomatic!
Why Cause Disease?
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Accident? Disadvantage? Advantage? To Whom?
Transmission; recruit host defenses; host constraints
The Pathogenic Scheme
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Entry (the portals)
Adherence
Avoidance of host defenses
—Invasion (intracellular life)
—Toxins
—Other means of subversion
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Multiplication
Persistence
Transmission
Pertussis
3 clinical phases:
Incub. Catarrhal
1 week 1-2 weeks
Paroxysmal
2-4 weeks
Convalescent
4-24 weeks
2-step pathogenesis scheme:
Adherence
Intoxication
Bordetella pertussis Colonization of
Respiratory Tract
Self-aggregation:
microcolony
Tropism: cilia
Host defense: ciliary
clearance, mucus production
Bacterial subversion of
host defense: paralyze
cilia, thicken mucus,
adhere to mucus
Host counterdefense:
programmed cell death!
Belcher CE, et al. Proc Natl Acad Sci U S A. 2000;97:13847-13852.
Outcomes of bacterial adherence
1. Colonization
2. Signaling
3. Delivery of toxins
4. Entry
5. Host cell cytoskeletal
rearrangements
Bacteria
The Tree of Life
(based on rRNA Sequences)
Archaea
Are there any
human pathogens
among Archaea?
Eukarya
Pace NR. Science. 1997;276:734-740
Why Are There No Known Archaeal Pathogens?
Opportunity?
„ Capability?
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– Microbial virulence
– Host response
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Detection
Eckburg PB, et al. Infect Immun. 2003;308:1635-1638.
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Chronic Infections
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More highly evolved form of host-parasite
relationship; co-adaptation
Microbial mechanisms: dormancy, differentiation,
specialized compartment, altered host cell
metabolism
Disease/host damage, due to error-prone
replication, recombination, new environmental
signals, misdirected host-immune response,
impaired host defenses
Chronic diseases of unclear cause:
role of microbes?
Examples at nonmucosal sites:
„ Coronary atherosclerosis
„ Sarcoidosis
„ Wegener’s granulomatosis
„ Kawasaki disease
„ Multiple sclerosis
„ Rheumatoid arthritis
„ Systemic lupus erythematosus
„ Polyarteritis nodosa
„ Some forms of cancer: breast, prostate, colon
Emergence of Infectious Diseases
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Acquisition of
toxins,adhesins
Antigenic variation,
e.g., new capsule
Broadened host range
Improved growth
or transmissibility
Acquisition of drugR
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Societal events: poverty, crowding,
conflict, migration
Globalization of food supply
Environmental changes
Human behavior: sexual, recreational,
diet, travel
Impaired host defenses, antibiotic use
Public health infrastructure
Evolutionary History of the Human-Microbe
Relationship: Summary
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Immense diversity of microbial life!
Humans and microbes have co-evolved for mutual
benefit; our microbiota are critical for health!
Pathogens constitute a small, specialized subset of the
human-adapted microbial world
Chronic disease may be a more common manifestation
of human-pathogen encounters than acute disease
Human activity threatens to destabilize our relationships
with the microbial world