Pathophysiology

1. Pathophysiology . Mechanisms of diseases .the physiology of abnormal statesordiseases . Pathophysiology can also mean the functional changes associated with or resulting from disease or injury. . Another definition is the functional changes that accompany a particular disease

2. PATHOPHYSIOLOGY OF INFECTIOUS DISEASES Mehtap KAÇAR MD. PhD Assist. Prof. Pathophysiologist Yeditepe University, Faculty of Medicine Department of Physiology

3. Learning Objectives: 1- Describe the relationships between humans and infectious agents, 2- Describe the mechanisms of infection and cellular injury by bacteria, viruses, and fungi, 3- Describe the clinical manifestations of infectious diseases. 4- Describe the septic shock.

4. Infectious Agents • Infectious diseases are the number one cause of death world-wide. • Dense populations in developing countries with poor sanitation are victims of plaque, cholera, malaria, tuberculosis, leprosy and schistosomiasis. • Only smallpox has been eradicated from the world by vaccination.

6. Microorganisms and Humans: A Dynamic Relationship • Many microorganisms find human bodies to be hospitable sites in which to grow and flourish; there they are provided with nutrients and the appropriate conditions of temperature and humudity. • These microorganisms are called the • “normal flora”. • They are found in different parts of body, including the skin, mouth, gastrointestinal tract, respiratory tract and genital tract.

7. The many relationships between humans and organisms: (box 9-1)

8. Stages of infection: • Four separate stages are associated with pathologic infection: • colonization, • invasion, • multiplication, • Spread. (Table 9-3)

10. Infection by a pathogen is influenced by several factors as listed below: • a- mechanism of action, • b- infectivity, • c- pathogenity, • d- virulence, • e- immunogenicity, • f- toxigenicity, • g- portal of entry.

11. a- Mechanism of action: • Direct damage of cells, interference with cellular metabolism and rendering a cell dysfunctional because of the accumulation of pathogenic substances and toxin production.

12. b- Infectivity • ability of the pathogen to invade and multiply in the host. • For example, coagulase, an enzymatic product of some pathogens that causes coagulation and allows some microorganism, such as staphylococci, to clot and form a sticky layer around themselves, protects the pathogens against host defenses.

13. c- Pathogenicity • Ability of an agent to produce disease – success depends on speed of pathogen reproduction, extent of tissue damage, and production of toxins.

14. d- Virulence • Potency of a pathogen meausered in terms of the number of microorganisms or micrograms of toxin required to kill a host. • For example, measles virus is low virulence; rabies virus is highly virulent.

15. e- Immunogenicity • Ability of pathogens to induce an immune response.

16. f- Toxigenicity • A factor important in determining a pathogen’s degree of virulence, that is, the ability to produce disease by production of a soluble toxin, such as hemolysin, leukocidin, other exotoxins and endotoxins. • For example: hemolysin destroys erythrocytes and leukocidin destroys leukocytes; both are products of streptococci and staphylococci.

17. g- Portal of entry • Route by which a pathogenic microorganism infects the host: • direct contact, • inhalation, • ingestion, • bites of an animal or insect.

18. Classes of infectious microorganisms • Infectious disease can be caused by microorganisms that range in size from 20 nm (poliovirus) to 10 m (tapeworm). • Table 9-4

20. Infection compartments 0

21. Pathogens cause damage to the host in three main ways: • 1- They may cause direct tissue injury to cells they enter or contact, either mechanically or chemically, or by interfering with normal cellular metabolism. • 2- microbial products may be toxic to host cells. (exotoxins, endotoxins) • 3- pathogens may cause the host immune system to damage host tissue (immunopathogenesis)

22. Direct Mechanisms of Pathogen-induced tissue Damage 0

23. Indirect Mechanisms of Pathogen-induced tissue Damage 0

24. Defense Mechanisms: • External defense • Internal Defense • Immune Defense

25. Protective Immunity To Microorganisms Defense against microbes is mediated by: Innate immunity and acquired immunity Humoral immunity (antibodies) Through both Cell mediated immunity (CMI)

26. Overview of Immune System Responses

27. innate host defense mechanisms • The first lines of defense against infectious microorganisms are external barriers, including the skin and mucous membranes and the cells and biochemicals of innate immunity. (Figure 9-1)

29. Cells of innate immunity express Toll-like receptors that recognize pathogens and activate inflammation and adaptive immunity, the second and third lines of defense. • Once a microorganisms penetrates the first lines of defense and invades the body the inflammatory response is initiated, especially the phagocytes. (figure 9-2)

31. Non-Specific Host Defense Mechanisms 1. First line of defense: a. Intact skin and intact mucous membranes as physical or mechanical barriers. b. Cellular and chemical factors. such as digestive enzymes, acidity of stomach (PH 1.5)and alkalinity of the intestine, acidity of vagina. c. Microbial antagonism by indigenous microflora; and overall nutritional status and state of health

32. 2. Second line of defense: a. Transferrin and lactoferrin, are tie up iron, thereby preventing pathogens access to this essential mineral. b. Fever, that augments host defense by stimulating leukocytes to deploy and destroy invaders, reducing available free plasma iron, and inducing the production of IL-1, which causes proliferation, maturation, and activation of lymphocytes in the immunologic response. Elevated body temperature also slow down the rate of growth of certain pathogens and can even kill some especially fastidious pathogens.

33. c. Interferons, are small , antiviral proteins that prevent viral multiplication in virus- infected cells and serve to limit viral infections. d. Inflammation, localized an infection prevent the spread of microbial invaders, neutralizes toxins, and aid in the repair of damaged tissue. e. Phagocytosis.

34. f. Complement system, involves approximately 30 different blood proteins that interact in a step-wise manner known as the complement cascade. Consequence of activation of the complement system: -- Initiation and amplification of inflammation. - Attraction and activation of leukocytes. - Lysis of bacteria and other foreign cells. - Increased phagocytosis by phagocytic cells.

35. 3. Specific Host Defense Mechanisms(third line of defense) • Immunology is the scientific study of the immune system and immune responses. • The immune system is the third line of defense against pathogens; it is a specific host defense mechanism. • Types of Acquired Immunity: 1. Active acquired immunity. 2. Passive acquired immunity.

36. Cells of the Immune System

37. Cells of the Innate (Non-specific) Immune System Phagocytes Monocytes/Macrophages PMNs NK cells Basophils and Mast cells Eosinophils Platelets Used with permission: Dr. Peter Darben, Queensland University of Technology

38. Phagocytic Cell Functional Responses Adhesion (localization) Chemotaxis (migration) Phagocytosis NADPH oxidase activation Lysosomal granule fusion: degranulation

39. Mechanism of Phagocytosis Macrophage

40. Cells that Link the Innate and Adaptive Immune Systems Antigen Presenting Cells (APCs) are a heterogenous population of leukocytes that play and important role in: Innate immunity Activation of helper T cells (Th cells) APCs are rich in class II MHC molecules Dendritic cells Macrophages B cells (not part of the innate immune system) Other cells (not part of the innate immune system)

41. Cells of the Adaptive (Specific) Immune System Lymphocytes B cells Plasma cells T cells Cytotoxic (Tc) Helper (Th) Th1 Th2 Used with permission: Dr. Peter Darben, Queensland University of Technology

42. Role of antibodies and complement system Antibodies are the primary defense against extracellular pathogens Neutralization

43. Antibodies are the primary defense against extracellular pathogens Neutralization Opsonization

44. Antibodies are the primary defense against extracellular pathogens Neutralization Opsonization Complement activation

45. The complement system, through the alternative and lectin pathways produces C3b, which attaches itself to the surface of the bacterium with carbohydrate capsules. • The C5b-C9 membrane lytic complex kills bacteria. • C3b functions as a highly effective opsonin that allows adherence between the bacterium and C3b receptors on the phagocyte’s surface, thus facilitating phagocytosis.

47. Pathogenic defense mechanisms • True pathogens have devised means to circumvent the host’s defenses. • Examples of these adaptations include surface coats that inhibit phagocytosis, surface receptors that bind to host cells, and toxins that damage cells or alter their function. • If the immune system is compromised, infections cannot be regulated.

49. Bacterial virulence and infectivity • Bacteria injure cells by producing desturictive enzymes (exotoxins) or endotoxins. • Exotoxins can damage the plasma membranes of host cells or prevent phagocytosis. • Endotoxins activate the inflammatory response and produce fever.

50. Exotoxins…. • They are proteins released during bacterial growth. • They are usually enzymes including; • -cytotoxins, • - neurotoxins, • - pneumotoxins, • - enterotoxins, • - hemolysins.