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MICR 201 Microbiology for Health Related Sciences
Lecture 9: Innate ImmunityEdith Porter, M.D.
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Lecture outline Concept of immunity
▪ Innate immunity ▪ Adaptive immunity
Innate immunity: first line of defense ▪ General aspects
▪ Physical factors▪ Chemical factors▪ Normal microbiota
▪ Cellular elements▪ Epithelial cells▪ Phagocytes
▪ Effector molecule▪ Complement▪ Antimicrobial peptides▪ Interferons▪ Iron binding proteins
Acute inflammation
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Concept of immunity
INNATE IMMUNITY
Functional at birth Rapid responses:
preformed or available within hours after infection
Limited specificity: pattern recognition via toll like receptors
Widely present in nature including in plants, invertebrates and vertebrates
ADAPTIVE IMMUNITY
Acquired, available within days
High specificity Memory In higher
vertebrates
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Overview of host defenses
First Line of Defense Second Line of Defense
• NK cells
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Physical (mechanical) defense of skin
Outer body surface
Keratin barrier
Epithelial cell shedding
Dryness
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Physical (mechanical) defense of mucosa
Inner body surfaces Mucus
Viscous
Protects underlying cells
Contains antimicrobial factors▪ Lysozyme
Constant fluid flow Tears
Saliva
Intestinal peristaltic
Urine production and urination
Vaginal secretions
Mucociliary clearance▪ 1 – 3 cm/h
Epithelial cell shedding
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Chemical defense
Sebum, unsaturated fatty acids
“antimicrobial lipids”
Low pH Skin (pH 3-5)
Stomach (pH 1.5 – 3)
Vagina (pH 3 – 5)
Urine (pH 6)
http://www.niams.nih.gov/Health_Info/Acne/images/normal.jpg
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Normal microbiota as part of host defense
Competes with potential pathogens for nutrients
Directly inhibits potential pathogens Lactobacilli: lactic acid, low pH Bacteriocins
Skin Tongue Esophagus
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Cellular elements of host defense
Epithelial Cells
Leukocytes
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Epithelial cells
Keratinizing in skin Non-keratinizing elsewhere
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Immune function of epithelial cells
Express toll-like receptors (TLR 1 –10) that recognize specific pathogen associated molecular patterns (PAMP) LPS PG
Produce antimicrobial peptides (AMP) Kill microbes
Secrete pro-inflammatory cytokines Alert the host
Epithelial cell defense
TLR
Microbial Products(LPS, PG, etc)
Antimicrobial Peptides
Cytokines 12
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Leukocytes in peripheral blood
Granulocytes
Monocytes Lymphocytes
Natural Killer Cells
Anti-viralAnti-bacterial Anti-fungal
Anti-parasiticAnti-allergic
Anti-bacterial Anti-fungal
B-Ly : antibody production
T-Ly: orchestrate
Anti-parasiticAnti-allergic
neutrophil eosinophil basophil
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Leukocytes in tissue
Macrophagein bone marrow Dendritic cell
Mast cell
Anti-parasiticAllergic responses
Communicates with
lymphocytes
Clears bacteria and fungi in
tissues
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Origin of leukocytes
All originate from bone marrow (red bone marrow)
Circulate in the body through vascular system and lymphatic system
Enter tissue as needed Some differentiate here and remain in
the tissue: macrophages, dendritic cells
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Performed by phagocytes (professional eaters) Neutrophils Monocytes Macrophages
Refers primarily to the uptake of bacteria and fungi
Relatively inefficient without special opsonins Opsonins are molecules that enhance
phagocytosis Make “food more edible” Host derived molecules that cover the
microbe and are recognized by phagocytes
Phagocytosis
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Phagocytes in Action
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Key steps of opsonophagocytosis (1)
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Key steps of opsonophagocytosis (2)
Chemotaxis Opsonization Adherence (attachment) Ingestion (engulfment)
Pseudopods Phagosome
Phagolysosome Killing and digestion
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Chemotaxis
Chemical attraction of phagocytes to microorganisms and movement of phagocytes towards the source of infection
Induced by chemoattractants: Microbial products (formyl-methionine-
peptides) Complement Cytokines (“Chemokines”)
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Opsonization
Phagocytes need their food (microorganisms) served on silver plates
Opsonines significantly enhance microbial uptake by phagocytes
Cover microbial surfaces and are recognized by specific receptors on phagocyte surfaces
Examples are: Antibodies Complement
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Killing and digestion by phagocytes
Oxygen dependent Oxidative Burst Reactive oxygen and reactive nitrogen
intermediates Oxygen-independent
Antimicrobial peptides Low pH Enzymes (Hydrolases, proteases,
phopholipases)
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Effector molecules of host defense
Complement system Kills and helps in phagocytosis
Antimicrobial Peptides: Kill
Interferons Strengthen basic host cell defenses
Iron binding proteins Expressed by both host and microbe Competition for iron
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Complement system
System of over 30 serum proteins Active components (C-) and inhibitors Widely distributed in body Many cells can synthesis complement
factors Major producers:
Hepatocytes (liver cells) Monocytes/macrophages Fibroblasts
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The Complement Cascade
Early events: proteolytic cascade generates bioactive cleavage fragments
C1 C4 C2 C3 C5 C6 C7 C8C9n
Late events: Protein polymerization generate a pore on target cell
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Activation of complement system
Classical pathway Antibodies bound to microbes change
conformation and open up binding sites for C1
Lectin pathway Sugar-binding molecule with similar structure
to C1 binds to the microbe and activate complement C2 and C4
Alternative pathway C3 binds directly to the microbial surface
aided by factors B, D, and P and activates C5
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Outcomes of Complement Activation
Always the samePore formation on microbe and direct
killing (C5b- C9n)Opsonization and improved
phagocytosis (C3b) Inflammation and recruitment of
phagocytes (C5a, C3a, C4a)
29Figure 16.9 (3 of 5)
Complement mediated enhancement of phagocytosis
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Pro-inflammatory action of complement
Action on blood vessels and Mast cells Dilation reddening and
heat Leakage of blood
components edema Make endothelial cells
and leukocytes sticky Transmigration of
leukocytes pus Chemoattractant for
leukocytes
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Microbial killing by complement C5b-C9n
1) Innate immunity isA) The body's ability to ward off diseases.B) The body's defenses against any kind of pathogen.C) The body's defense against a particular pathogen.D) The lack of resistance.E) Increased susceptibility to disease.
2) The complement protein cascade is the same for the classical pathway, alternative pathway, and lectin pathway beginning with the activation ofA) C1.B) C2.C) C3.D) C5.E) C6.
3) Which of the following does NOT increase blood vessel permeability?A) KininsB) ProstaglandinsC) LysozymesD) HistamineE) Leukotrienes
4) Which of the following does NOT provide protection from phagocytic digestion?A) Preventing formation of phagolysosomesB) Killing white blood cellsC) Causing formation of phagolysosomesD) Ability to grow at a low pHE) Biofilms
Practice questions
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Antimicrobial peptides
Found in phagocytes and epithelial cells
Small (< 100 amino acids) Cationic
positive net charge at physiological pH
Arginine and/or lysine rich Amphiphilic: also
hydrophobic domains Microbial killing through
membrane permeabilization and other mechanisms Example: defensins
+ + ++ + +
+ + +
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Interferons (IFN a and IFN )b : act on host cells to increase production of antiviral proteins
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Iron binding proteins
Host derived proteins Transferrin: blood and tissue fluid Lactoferrin: milk, saliva, mucus
Bind iron which is essential to microbe Microbes counteract with siderophores
or iron binding protein receptors
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Acute inflammation
Relatively uniform response to a variety of causes Infection Physical agents like heat, radiation etc Chemical agents like acids, bases etc.
Key signs are rubor (redness), dolor (pain), calor (heat), and tumor (swelling)
Local response includes vasodilation and increase of permeability, phagocyte migration and phagocytosis, tissue repair
Systemic response mediated by TNFa and acute phase proteins like C-reactive protein up to 1000x fold increased) can lead to fever, shock, disseminated coagulation
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Process of acuteinflammation
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Important to remember
Innate immunity is widely conserved, functional upon birth, operates via pattern recognition and TLR, has no memory
Key cells in innate immunity are epithelial cells and phagocytes
Phagocytosis is enhanced by opsonins Phagocytes kill via oxygen radicals, antimicrobial
peptides, low pH, and enzymes. The effector molecules of innate immunity are
complement (killing, inflammation, enhanced phagodytosis), antimicrobial peptides (killing), interferons (activation of host antiviral defenses), and iron binding proteins (deprive microbes of iron).
W2011 MICR 450 Innate Immunity (4)
Prerequisites: One of the following; MICR 201+MICR 202, MICR 300, BIOL 380, or instructor consent. Questions? email/call Dr. Edith Porter at eporter@calstatela.edu , (323) 343 6353 or drop by at ASCL 355
First line defense from concept to moleculesEmphasis on primary research and hands on training in current
methods in innate immunology including flow cytometry
Lec: MW 9:50 - 10:40 am * Lab: M 10:50 – 2:20 pm * Rec: W 10:50 – 11:40 am
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