1. Pathogenesis of Infectious Diseases BY Prof. DR. Zainalabideen A. Abdulla, DTM&H., MRCPI, Ph.D., FRCPath. (U.K.)

2. Learning Objectives

3. Infection versus Infectious Diseases Patho from path = Disease Pathogenicity = Ability to cause a disease Pathogenesis = Steps/mechanisms involved in development of a disease Infection = Colonization by a pathogen, but NOT necessary to have infectious disease (WHY?)

4. Why infection does not always occur Microbes are unable to multiply e.g. respiratory microbes on the skin Lack of a specific tissue receptor for microbes Antibacterial factors, e.g. Lysozymes Indigenous microbiota, e.g. Bacteriocins Overall health status Immunity and vaccination Phagocytosis: In blood and tissues

5. Periods/Phases of infectious diseases 1. Incubation Period Pathogen arrival Symptoms Onset 2. Prodromal Period: Out of sort/No symptoms 3. Period of illness: Symptoms/Communicable 4. Convalescent: Recovery; may be long or with tissue damage

7. Localized vs systemic infections Localized infections, e.g. boils, abscesses Systemic infection: Localized Spread by blood, lymph or phagocytes (wondering) e.g. Mycobacterium tuberculosis spread to internal organs is called military tuberculosis (disseminated)

8. Acute, Subacute, and Chronic diseases Acute disease: Rapid onset; Rapid recovery e.g. Measles, mumps Chronic disease: Slow onset; Lasts a long time e.g. Tuberculosis, Leprosy Subacute disease: More sudden that chronic, less than acute e.g. Subacute endocarditis (SAE)

9. Symptoms vs Signs of a disease Symptoms: Subjective evidence experienced or perceived by patients, pain, itching, nausea, etc Symptomatic disease: Clinical disease “with” Asymptomatic disease: Subclinical “unaware” Example: N. gonorrheae: Male: Symptomatic Female: Asymptomatic Trichomonas vaginalis: Reverse Signs: Objective evidence of a disease detected by clinicians, e.g. hepatomegaly, heart rate, etc

10. Latent infection Latent = Lie hidden Latent disease: Dormant ( Not currently manifest ) Symptomatic Asymptomatic Symptomatic Examples: - Human Herpes Virus (HHV) type 1 Cold Sore or HHV type 2 Genital - HHV type 3 (Chickenpox Shingles) - Syphilis ( Spirochete : Treponema pallidum )

13. Primary vs Secondary Infections One infectious disease follows another First: Primary infection Second: Secondary infection Example: Primary: Mild viral respiratory infection (damage respiratory ciliated epithelium) Secondary: Pneumonia; due to inhaled: Streptococcus pneumonia Haemophilus influenzae

14. Steps in pathogenesis of infectious disease 1. Entry (different routes) 2. Attachment 3. Multiplication (Local or systemic) 4. Invasion or spread 5. Evasion (avoid) of host defenses 6. Damage to host tissue (s) N.B.: Not always ALL steps involved

16. Virulence Synonym to Pathogenic (Virulent) Disease Nonpathogenic (Avirulent) NOT Toxigenic (virulent), e.g. C. diphtheria Encapsulated (virulent), e.g. S. pneumoniae Some pathogens are more virulent than others e.g. Shigella > Salmonella Strains more pathogenic than others of the same pathogen, e.g. S. pyogenes producing erythrogenic toxin (causes scarlet fever)

18. Virulence Factors Attachment: Receptors (integrin) on tissues: - Glycoprotein - S. pyogenes: Adhesin (Protein F) - HIV: CD4 receptor Adhesin (Ligand) on pathogens: - HIV: Glycoprotein gp 120 CD4

20. Bacterial Fimbriae (Pili) Hairlike, flexible projections Proteins (Pilin) Attach to surfaces Example: N. gonorrheae: To Urethra E.coli: Bladder S. pyogenes M protein: - Adhere to pharyngeal epithelium - Anti-phagocytic

21. Obligate intracellular pathogens G- : Rickettsia (endothelial cells) Chlamydia (Respiratory/genital epith. Eye conjunctiva) Malaria: Plasmodium (RBC) Facultative intracellular pathogens Extracellular and intracellular existance e.g. in phagocytes & on culture media

22. Intracellular survival mechanisms Phagocytes: Macrophages & neutrophils e.g. M. tuberculosis: Wax (protect m.o. from destruction inside phagocytic cells); Table Capsules Anti-phagocytic (unable to engulf) e.g. Streptococcus pneumoniae Haemophilus influenzae Klebsiella pneumoniae

24. Flagella Motile bacteria: So invade aqueous areas Anti-phagocytic Exoenzymes Necrotizing enzymes, coagulase, kinases, hyaluronidase, collagenase, hemolysins and lecithinase Some pathogens produce also toxins e.g. S. pyogenes

25. Necrotizing enzymes Destroy tissues - Clostridium perfringens causes gas gangrene (myonecrosis) by proteases and lipases - S. pyogenes (flesh-eating strain) causes necrotizing fasciitis Coagulase Staphylococcus aureus feature Binds prothrombin Staphylothrombin Clot plasma Protect themselves by fibrin coat against Ab and phagocytosis

27. Kinases Fibrinolysins (vs coagulase) Example: - Streptokinase of Streptococci (used to treat coronary thrombosis) - Staphylokinase of Staphylococci Hyaluronidase Spreading factor Breaks hyaluronic acid of connective tissue Staphylococcus, Streptococcus, Clostridium

28. Collagenase Breaks collagen (tendon, cartilage, bones) Example: C. perfringens Hemolysins Destroy RBC Iron to pathogens Types of hemolysis (alpha, beta, gamma)

29. Lecithinase Breaks phospholipids (Lecithin) as of RBC Example: C. perfringens Toxins 1. Endotoxin 2. Exotoxins

30. Endotoxin Septicemia (sepsis) G- cell wall (Lipid A of Lipopolysaccharides) Fever (caused by pyrogens) Septic shock: Inadequate blood supply to vital organs Exotoxin Poisonous proteins Neurotoxins, enterotoxins, cytotoxins, exfoli- ative toxin, erythrogenic toxin, diphtheria toxin

31. cont./… exotoxins Neurotoxins Affect CNS Clostridium tetani (Tetanospasmin effect: spastic, rigid paralysis); Figure Clostridium botulinum (generalized flaccid paralysis) Enterotoxins Cause diarrhea and vomiting E. coli, Shigella, Salmonella, C. perfringens C. difficile (Toxin A and B)

33. Toxic Shock syndrome : 1. Staphylococcus aureus (common cause) TSST-1 affects integrity of capillary wall 2. Streptococcus pyogenes (less common) Exfoliative (epidermolytic) toxin S. aureus Scaled Skin Syndrome Erythrogenic toxin S. pyogenes Scarlet fever

34. Leukocidin Destroy leukocytes (WBC)/the phagocytes Staphylococci, Streptococci, Clostridia Diphtheria toxin Corynebacterium diphtheria Inhibits protein synthesis Kills mucosal epithelial cells & phagocytes Affects heart and nervous system Coded for by bacteriophage gene (infected)