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Evolutionary History of the Human-Microbe Relationship David A. Relman, MD Evolutionary History of the Human-Microbe Relationship 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 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? 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 * SPECIES * GENUS * FAMILY CLASS PHYLUM Palmer C, et al. Nucl Acids Res. 2006;34:e5 Colonization of the Newborn Intestinal Tract 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 Brugia malayi and other filariae are colonized by endosymbiotic bacteria: Wolbachia spp. Elimination of these bacteria renders the filariae nonviable and sterile! 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... 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? Accident? Disadvantage? Advantage? To Whom? Transmission; recruit host defenses; host constraints The Pathogenic Scheme Entry (the portals) Adherence Avoidance of host defenses —Invasion (intracellular life) —Toxins —Other means of subversion 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? – Microbial virulence – Host response Detection Eckburg PB, et al. Infect Immun. 2003;308:1635-1638. 26-MB Ô 24-MB Ó 22-MB Ó 26 Ô 26 Ô 24 Ó 22 Ó Chronic Infections 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 Acquisition of toxins,adhesins Antigenic variation, e.g., new capsule Broadened host range Improved growth or transmissibility Acquisition of drugR 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 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