NONSPECIFIC DEFENSES OF THE HOST

1. NONSPECIFIC DEFENSES OF THE HOST

2. Innate Immunity (Non-Adaptive Immunity) (Pre-existing immunity) Immunity you are born with Does not change/adapt during life in response to infection

3. HOST IMMUNE SYSTEM There are over 400 known pathogens of man and each of us is likely to come into contact with at least 150 of them within our life span Include: • Viruses (10-20 nm) • Bacteria (1-2 um) • Protozoa (50-100um) • Fungi (10um-10cm) • Parasites (Worms & Flukes) (>10cm)

4. Why Do We Need An Innate Immune System? Replication rate of extracellular bacteria with an average doubling time of 20 minutes Dead within 24hrs !!! = 2 x 1021

5. Innate Immune System comprises of a Cellular arm(cells) and a Humoral arm (soluble factors)

6. IMMUNOLOGY Study of how the body limits invasion by non-self and recognises and eliminates altered self - damaged cells and cancer cells HAEMATOLOGY Study of blood cells and their origins and the homeostatic mechanisms that control coagulation Most types of blood cell are components of the immune system

7. INFECTION • Differences between infectious agents and • their sites of replication necessitate • different immune mechanisms for their control • VIRUSES (DNA & RNA, intracellular replication) • BACTERIA (intracellular / extracellular replication) • FUNGI • PROTOZOA • WORMS

8. DEFENCE AGAINST INFECTION • Physical barriers • Non-adaptive (Innate) immunity • Adaptive immunity

9. NONSPECIFIC RESISTANCE • Defenses that protect the host against ANY pathogen • Mechanical factors • Chemical factors

10. Specific Resistance Specific Resistance, or immunity is based on antibody production It is a defense against a particular microorganism

11. Mechanical Factors The intact skin consists of the dermis, an inner thicker portion composed of connective tissue, and the epidermis, an outer, thinner portion consisting of several layers of epithelial cells The top layer of epidermal cells contains the protein keratin (remember—fungi produce keratinase)

12. SKIN • Dermis • Inner thicker portion • Epidermis • Outer, thinner portion • Keratin (waterproofing)

13. SKIN INFECTIONS • Rare in unbroken skin • Sweat washes microbes off • Cuts and burns may get infected • Subcutaneous infections • Staphylococcus spp.

14. MUCOSAL SURFACES • Epithelial layer • Connective tissue Bronchi Intestine

15. MUCOSAL SURFACES (cont.) • Gastrointestinal tract • Respiratory tract • Urinary tract • Reproductive tract

16. MUCOSAL SURFACES (cont.) • Mucus traps microorganisms • Physical barrier • Cilia lower respiratory tract • Washing (sweat)

17. MUCOSAL SURFACES (cont.) • Mucosal irritation or damage facilitates infection (smoking) • Substances produced by pathogens • Treponema pallidum

18. Flushing of Cavities • Prevents colonization • Tears (lysozyme—breaks down NAG/NAM) • Saliva • Urine • Feces • Sebum (unsaturated fatty acids of sebum inhibit growth of certain pathogens)

19. CHEMICAL FACTORS • Skin • Sebaceous glands • Unsaturated fatty acids • pH 3-5

20. LYSOZYME • Enzyme that degrades peptidoglycans • Gram positives more susceptible than Gram negatives

21. LYSOZYME (cont.) • Sweat • Saliva • Tears • Nasal secretions

22. GASTRIC JUICE • Hydrochloric acid (pH 1.2 to 3) • Helicobacter pylori • Neutralizes acidic pH • Enzymes • Mucus

23. BLOOD • Iron-binding proteins • Lactoferrins • Transferrins • Iron unavilable for pathogens

24. DEAD TISSUE leads to INFECTION Mechanical, chemical or thermal injury Debride wounds Interruption of blood supply – infarction

25. DEFENCE AGAINST INFECTION • Physical barriers • Non-adaptive (Innate) immunity • Adaptive immunity A variety of immune mechanisms utilising proteins and cells that act in concert to control and eradicate infection Immune mechanisms are targeted by molecular recognition of micro-organisms

26. INNATE IMMUNITY • Mast cells • increase blood flow and vascular permeabilitybring components of immunity to site of infection • Phagocytes • engulf (phagocytose) and destroy micro-organisms • Complement • activate mast cells, attract phagocytes, opsonize • and lyze micro-organisms • Acute phase proteins • activate complement and opsonise

27. 1011 different receptors 1011 different antigens 1 3 1 3 2 2 4 4 SPECIFIC IMMUNITY For each different antigen there is a specific receptor

28. Exposure to infection Resistance to infection • Climate • Vectors • Population • Housing • Water / sewage • Public health • Mutation • Age • Previous exposure • Vaccination • Nutrition • Disease • immunodeficiency

30. PHAGOCYTOSIS is the body’s second line of defense • Ingestion of particulated matter by a cell • Phagocytes (white blood cells) • Phagocytosis derived from the Greek work “to eat” and “cell”

31. Formed Elements in Blood --Blood fluid is called plasma --Cells and cell fragments of the blood are the formed elements --Most important ones in Immunology are the leukocytes (WBC) --Decreased leukocyte counts are called leukopenia (I.e.Thrombocytopenia)

32. A differential white blood count detects leukocyte number changes Leukocytes are subdivided into three categories GRANULOCYTES---have granules in their cytoplasm (neutrophils, basophils, eosinophils) LYMPHOCYTES (are note phagocytic—occur in lymphoid tissue) MONOCYTES (lack granules & are phagocytic only after maturing into MQ)

33. PHAGOCYTES • Neutrophils (60-70%) • Initial phagocytic cells • Monocytes/Macrophages (3-8%) • Final phagocytic cells

34. Granulocytes Eosinophil (0-2%) Neutrophils (45-74%) In Blood

35. Eosinophils Target – Worms and flukes Filarial Nematode Larvae Wucheria bancrofti Migrates within tissues

36. Granulocytes are mostly neutrophils that wander in the blood and can pass through capillary walls to reach trauma sites MQ are highly phagocytic cells called wandering MQ’s b/c of their ability to migrate Fixed MQ’s (histiocytes) enter tissue/organs and remain there (I.e. Kupffer cells in the liver)

37. PHAGOCYTOSIS • Chemotaxis • Adherence • Ingestion • Digestion

38. Avoiding Contact with Phagocytes • Bacteria can avoid the attention of phagocytes in a number of ways • Pathogens may invade or remain confined in regions inaccessible to phagocytes. Certain internal tissues (e.g. the lumens of glands, the urinary bladder) and surface tissues (e.g. the skin) are not patrolled by phagocytes. • Some pathogens are able to avoid provoking an overwhelming inflammatory response. Without inflammation the host is unable to focus the phagocytic defenses.

39. Some bacteria or their products inhibit phagocyte chemotaxis For example, Streptococcal streptolysin suppresses neutrophil chemotaxis, even in very low concentrations Fractions of Mycobacterium tuberculosis are known to inhibit leukocyte migration.

40. Some pathogens can cover the surface of the bacterial cell with a component which is seen as "self" by the host phagocytes and immune system. Such a strategy hides the antigenic surface of the bacterial cell. • Phagocytes cannot recognize bacteria upon contact and the possibility of opsonization by antibodies to enhance phagocytosis is minimized. • Staphylococcus aureus produces cell-bound coagulase which clots fibrin on the bacterial surface • Treponema pallidum, the agent of syphilis, binds fibronectin to its surface. • Group A streptococci are able to synthesize a capsule composed of hyaluronic acid. Hyaluronic acid is the ground substance (tissue cement) in connective tissue.

41. CHEMOTAXIS • Chemical attraction of phagocyte to microorganism • Microbial products • Damaged tissue • White blood cell components

42. ADHERENCE & ENGULFMENT (INGESTION) • Attachment of phagocyte plasma membrane to microorganism

43. INGESTION • Pseudopods extend from phagocyte plasma membrane and engulf the microorganism forming the phagosome

44. A pathogen is only a pathogen if it “tricks” the immune system’s defense missiles (phagocytes)

45. Inhibition of Phagocytic Engulfment • Some bacteria employ strategies to avoid engulfment (ingestion) if phagocytes do make contact with them • Many important pathogenic bacteria bear on their surfaces substances that inhibit phagocytic adsorption or engulfment • Clearly it is the bacterial surface that matters • Resistance to phagocytic ingestion is usually due to a component of the bacterial cell surface (cell wall, or fimbriae, or a capsule).

46. Classical examples of antiphagocytic substances on the bacterial surface include • Polysaccharide capsules of S. pneumoniae, Haemophilus influenzae, Treponema pallidum and Klebsiella pneumoniae • M protein and fimbriae of Group A streptococci • Surface slime (polysaccharide) produced as a biofilm by Pseudomonas aeruginosa • O polysaccharide associated with LPS of E. coli • K antigen (acidic polysaccharides) of E. coli or the analogous Vi antigen of Salmonella typhi

47. DIGESTION • Within cytoplasma the phagosome fuses with lysosome (digestive enzymes) forming the phagolysosome

48. Lysozyme Lipases Proteases Hypochlorous acid Toxic O2 Nucleases LYSOSOME CONTENTS

49. Survival Inside of Phagocytes Some bacteria survive inside of phagocytic cells, in either neutrophils or macrophages Bacteria that can resist killing and survive or multiply inside of phagocytes are considered intracellular parasites In this case, the environment of the phagocyte may be a protective one, protecting the bacteria during the early stages of infection or until they develop a full complement of virulence factors The intracellular environment guards the bacteria against the activities of extracellular bactericides, antibodies, drugs, etc.

50. BACTERIAL INTRACELLULAR PATHOGENS