1. General Microbiology (Micr300) Lecture 14 Overview of Host Defenses Innate Immunity (Text Chapter: 22.1-22.2)

2. Overview of Host Defenses

3. Definitions Immunity is the ability of an organism to resist infection Innate immunity is the ability to recognize patterns of microbes and their products and to eliminate microbes with either preformed or rapidly made available effectors. It does not rely on previous exposure to a pathogen or its products. Adaptive immunity (antigen-specific immunity) is the acquired ability to specifically recognize and destroy an individual pathogen or its products and rely on its previous exposure to the pathogen or its products.

4. Two Arms of Host Defenses Innate Immunity Functional at birth Preformed or available within hours post infection Pattern recognition Widely present in nature including plants, invertebrates and vertebrates Adaptive Immunity Acquired Available within days Highly specific Memory

5. The Key Players of Host Defenses InnateAdaptive CellularPhagocytes Epithelial cells Natural Killer cells Lymphocytes SolubleComplement Antimicrobial peptides Antibodies

6. Cells and Organs of the Immune System The majority of the cells involved in immunity originate from hematopoietic stem cells in the bone marrow (Figure 22.1). The blood and lymph systems (Figure 22.2) circulate cells and proteins that are important for a functional immune system. Whole blood is composed of plasma, a liquid containing proteins and a variety of other solutes and suspended cells. There are red blood cells or erythrocytes, which carry hemoglobin, and white blood cells or leukocytes which are mediating immunity.

7. Origins of Major Cells Involved in Immune Response Memory cells Myelyoid Cells Lymphoid Cells

8. Blood and Lymph Systems

10. Organs with Immune Functions Bone marrow Thymus Spleen Lymph nodes MALT and GALT

11. Overview of Immune Response

12. Innate Immunity

13. The Key Players of Host Defenses InnateAdaptive CellularPhagocytes Epithelial cells Natural Killer cells Lymphocytes SolubleComplement Antimicrobial peptides Antibodies

14. Complement System of over 20 serum proteins Active components (C-) and inhibitors Early events: proteolytic cascade generates bioactive cleavage fragments Late events: Protein polymerization generate a pore on target cell

15. Complement Is Multifunctional Antigen-Antibody (Classical) Collectin Microbial Surfaces (Alternative) Membrane Attack Complex (Pore) Neutrophil recruitment Opsonization Vasoactive Inflammation

16. The Complement Pore Bhakdi et al

17. Antimicrobial Peptides Wide spread in nature Gene-encoded Small (< 100 amino acids) Cationic positive net charge at physiological pH Arginine and/or lysine rich Amphiphilic: contain both hydrophilic and hydrophobic domains

18. Antimicrobial Peptides Act Through Pore Formation Alex M. Cole - - - - - - - - - - + +

19. Membrane Targeted Activity of Antimicrobial Peptides Electron micrograph of Neisseria gonorrhoeae after treatment with antimicrobial peptides: -+-+ Qu et al

20. Phagocytes Important mediators of the innate immune response are phagocytes Phagocytes are primarily involved in taking up (phagocytosis) and killing microbes Phagocytes recognize microbes through a broad range of receptors Pathogen-associated pattern molecules Opsonines

21. Phagocytes (Professional Eaters) Neutrophil Granulocytes Monocytes Macrophages Granulocyte after phagocytosis of S. aureus Granulocyte in action: uptake of Candida

22. Opsonins Opsonins significantly enhance microbial uptake by phagocytes Cover microbial surfaces and are recognized by specific receptors on phagocyte surfaces Examples are: Antibodies Complement cleavage product

23. Major Steps in Opsonophagocytosis 1.Opsonization 2.Attachment 3.Engulfment 4.Phagosome formation 5.Phagolysosome formation 6.Killing and digestion 1. 2./3. 4. 5. 6.

24. Killing and Digestion by Phagocytes Reactive oxygen and reactive nitrogen intermediates Antimicrobial peptides Low pH Hydrolases, proteases, phopholipases

26. Inflammation, Fever, and Septic Shock Inflammation is characterized by pain (dolor), swelling (tumor), redness (rubor), and heat (calor). The local inflammatory response is a normal and generally desirable outcome of an immune response. Uncontrolled systemic inflammation, called septic shock, can lead to serious illness and death. The first inflammatory cell to arrive at the scene of an infection or tissue injury is the neutrophil, shortly thereafter monocytes that become macrophages. These cells are attracted to the site of an active infection or tissue injury by soluble chemoattractants.

27. Activated Macrophage

28. Natural Killer Cells Large granular lymphocyte-like cells Lyse target cells Important in infections with viruses and intracellular organisms

29. Epithelial cells SkinMucosa

30. Epithelial Cells are Defense Cells Express toll-like receptors (TLR 1 –10), that recognize specific pathogen assocated molecule patterns TLR-2: Peptidoglycan TLR-4: LPS TLR-9: Flagella Produce antimicrobial peptides Secrete pro-inflammatory cytokines