1. Lecture 19 Host Defense Against Infection
Innate immunity
Adaptive Immunity
In this lecture you should develop a sense of how innate and adaptive immunity are interrelated.
How does the nature of the innate response influence the subsequent adaptive response?

2. Response to Initial Infection

3. Stages of Response to Infection

4. Course of Typical Acute Infection

5. Innate Host Defense Mechanisms
Anatomic Factors
Mechanical Factors
Biochemical Factors
The material on anatomical and mechanical factors will not be covered in class due to time limitations. You are responsible for the concepts.

6. Skin Stratified and cornified epithelium provides a mechanical barrier
Indigenous microbiota competes with pathogens
Acid pH inhibits growth of disease producing bacteria
Bactericidal long chain fatty acids in sebaceous gland secretions

7. Respiratory Tract Upper Respiratory Tract Lower Respiratory Tract
Nasal hairs induce turbulence
Mucous secretions trap particles
Mucous stream to the base of tongue where material is swallowed
Nasal secretions contain antimicrobial substances
Upper respiratory tract contains large resident flora
Lower Respiratory Tract
Particles trapped on mucous membranes of bronchi and bronchioles
Beating action of cilia causes mucociliary stream to flow up into the pharynx where it is swallowed
90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoli
Alveoli
Alveolar macrophage rapidly phagocytize small particles

8. Alimentary Tract General defense mechanisms Stomach Small Intestine
Mucous secretions
Integrity of of mucosal epithelium
Peristaltic motions of the gut propel contents downward
Secretory antibody and phagocytic cells
Stomach
Generally sterile due to low pH
Small Intestine
Upper portion contains few bacteria
As distal end of ilieum is reached flora increases
Colon
Enormous numbers of microorganisms
50-60% of fecal dry weight is bacteria

9. Genitourinary Tract Male Female (Vagina)
No bacteria above urethrovesicular junction
Frequent flushing action of urine
Bactericidal substances from prostatic fluid
pH of urine
Bladder mucosal cells may be phagocytic
Urinary sIgA
Female (Vagina)
Large microbial population (lactobacilli)
Microorganisms produce low pH due to breakdown of glycogen produced by mucosal cells

10. Eye
Flushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynx
Tears contain a high concentration of lysozyme (effective against gram positive microorganisms

11. Innate Immune Recognition
All multicellular organisms are able to recognize and eliminate pathogens
Despite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs)
Host cells do not share PAMPs with pathogens
PAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)

12. Three Functional Classes of PRRs/PRMs
Endocytic receptors
Macrophage mannose receptor
Macrophage scavenger receptor (SR)
Integrin CD11b:CD18
Secreted proteins
Mannose-binding protein/lectin
Pulmonary surfactant proteins A and D
C-reactive protein (CRP)
Signaling receptors
Toll receptor family

13. Endogenous Signals Induced by PAMPs
Mediate inflammatory cytokines
Interleukin-1 (IL-1)
IL-6
Tumor necrosis factor (TNF-a)
Type 1 interferon (INF-I)
Major effector cytokines
Chemokines
Antigen-presenting cells recognize PAMPs
Same APC processes pathogens into specific pathogen-derived antigens and presents them with MHC encoded receptors to T-cells
T-cell responds only when presented with both signals
Different Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2)

14. Antimicrobial Peptides/Defensins
Four hundred peptides described to date
Defensins (3- 5-kD, four families in eukaryotes)
a-defensins (neutrophils and intestinal Paneth cells)
b-defensins (epithelial cells)
Insect defensins
Plant defensins
Defensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane permeability.
May also play a role in inflammation and wound repair

15. Complement System Three pathways now known
Classical
Alternative
Lectin or MBL pathway (binding to mannose-containing carbohydrates)
Host cells have complement regulatory proteins on their surface that protect them from spontaneous activation of C3 molecules

16. Inflammatory Mediators in Innate Immunity
Cytokines secreted by phagocytes in response to infection include:
IL-1
activates vascular endothelium and lymphocytes
Increases adhesiveness of leukocytes
IL-6
Induces B-cell terminal maturation into Ig-producing plasma cells
IL-8
Induces expression of b2 integrin adhesion molecules on neutrophils, leading to neutrophil migration to infection site
IL-12
Activates NK cells and induces Th1-cell differentiation
IL-18
TNF-a
Activates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissues

17. Other Mediators and Molecules
Phagocytes
Toxic oxygen radicals
Peroxides
Nitric oxide (NO)
Lipid mediators of inflammation
Prostaglandins
LTB4
Platelet activating factor
Complement component C5a
Stimulates mast cells to release histamine, serotonin and LTB4
IL-1, IL-6 and TNF-a
Induce acute-phase response in liver
Induce fever
IL-1 and IL-18 signaling pathways activate NF-kB, important in innate immunity

18. Immune Cells and Innate Immunity
Phagocytes
Neutrophils
Moncyte/macrophage
Eosinophils (to a lesser extent)
NK cells (large granular lymphocytes)
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Have two major functions
Lysis of target cells
Production of cytokines (IFN-g and TNF-a)
Act against intracellular pathogens
Herpesviruses
Leishmania
Listeria monocytogenes
Act against protozoa
Toxoplasma
Trypanasoma

19. Immune Cells and Innate Immunity (cont’d)
g/d T cells
Two types of T cell receptors
One composed of a and b chains (basic T cell antigen receptor)
One composed of g and d chains (minor population of T cells)
Two groups of g/d T cells
One group found in lymphoid tissues
One group located in paracellular space between epithelial cells
Recognizes unprocessed target antigen in absence of APC help
B-1 cells (minor fraction of B cells, do not require T-cell help)
Mast cells
Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glands
Capable of phagocytosis
Process and present antigen using MHC class I or II receptors
LPS can directly induce release of mast cell mediators
Complement (C3a and C5a) induce mast cells to release mediators
Chemotaxis, complement activation, inflammation
TNF-a secreted by mast cells results in neutrophil influx into infected site

20. Summary of Innate Immunity
External and mechanical barriers
Receptors for pathogen motifs
Soluble antimicrobial proteins
Pattern of cytokines produced influences adaptive response

21. Adaptive Immunity and Infection

22. Protective Role of Antibodies Against Pathogens
Toxin neutralization
Opsonization/enhancement of phagocytosis
Sensitization for killing by NK cells
Sensitization of mast cells
Activation of complement system

23. Toxin Neutralization

24. Diseases caused by bacterial toxins

25. Preventing Bacterial Adherence

26. Virus-blocking Antibodies

27. Activation of the Complement Cascade
Cell Activation (anaphylatoxins)
Activate inflammatory cells
Induce smooth muscle contraction and blood vessel permeability
Cytolysis ("membrane attack complexes“)
Loss of cell membrane integrity
Opsonization
Complement receptors on phagocytic cells
Renders cells vulnerable to phagocytosis
Study Guide
What are immune adherence and opsonization?
Why would a chemotactic factor be important in inflammation?
What is the basis for chemotaxis?

28. Fc Receptors

29. Opsonization and Immune Adherence
C3B (C4B)
Facilitates adherence of bacteria, viruses and neutrophils to monocytes and macrophages
Facilitates ingestion of certain bacteria by neutrophils and monocytes
Facilitates ingestion by activated macrophages
Augments mediated phagocytosis and IgG-mediated cell cytotoxicity (ADCC)
Antibody
antibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherence
Study Guide
What is the immune adherence receptor? On what cell type is it found?

30. Chemotaxis Site of inflammation, tissue damage and immune reactions
capillary blood vessel
phagocyte
endothelium
basement membrane
Site of inflammation, tissue damage and immune reactions
PAVEMENTING
C5a
DIAPEDESIS
Study Guide
Why does the granulocyte migrate out of the vessel?
CHEMOTAXIS

31. Phagocytosis

32. Bactericidal Agents in Phagocytic Cells

33. Natural Killer Cells and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

34. Inflammation Increased blood supply to the infected area
The four cardinal signs of inflammation (Cornelius Celsus, 30 BC to AD 38):
rubor et tumor cum calore et dolore
redness and swelling with heat and pain
Increased blood supply to the infected area
Increased capillary permeability
Migration of leukocytes into tissues (Chemotaxis)
What are the characteristic signs of inflammation?
What is responsible for them?