1. Infectious Diseases Amelia Co-Fibra MD, FPSP

2. Tell me

3. How is this possible?

5. UNDERSTANDING PATHOGENESES OF INFECTIOUS AGENTS 1. Enumerate the categories of Infectious agents and their general features 2. Know the different human barriers against infectious agents 3. To enumerate and understand the Transmission & Dissemination of microbes 4. To know how microbes cause disease A. VIRAL INJURY B. BACTERIAL INJURY C. INJURIOUS EFFECTS OF HOST IMMUNITY COURSE OUTLINE

6. KNOW DISEASES PRODUCED BY SOME OF THE INFECTIOUS AGENTS A. VIRAL INFECTION B. BACTERIAL INFECTION C. PARASITES D. FUNGAL COURSE OUTLINE

7. Categories of Infectious Agents PRIONS VIRUSES BACTERIOPHAGES/ PLASMIDS/ TRANSPOSON BACTERIA CHLAMYDIA / RICKETTSIAE/ MYCOPLASMA FUNGI PROTOZOA HELMINTHS ECTOPARASITES

8. Classes of Human Pathogens

9. PRIONS Nucleic acid free Spontaneous mutation or Inherited Mutation in PrP Cause Transmissible Spongiform Encephalitis

10. Pathophysiology Abnormal PrP promotes transformation of normal PrP to abnormal forms EXPLAINING THE INFECTIOUS NATURE OF THESE DISEASE

11. Cause Transmissible Spongiform encephalitis Kuru ( Human Cannibalism ) Bovine Spongiform Encephalitis ( Mad Cow Disease ) Creutzfeldt-Jacob Disease (Spontaneous - Sporadic/ Inherited -Familial) Transmitted From corneal/ organ transplant BSE infected cattle Blood Transfusion Vacuolization of gray matter but no inflammation Clinical presentation

12. Obligate Intracellular 20-300nm May aggregate forming inclusion bodies CMV – large eosinophilic inclusion Nucleic acid core surrounded by capsid Cause Transient illness ( colds, influenza) Not eliminated  persist w/in cells Continue to multiply ( HEPATITIS B ) Non-replicating OR Latent ( chickenpox shingles) May transform host cell  tumor / cancer cell ( Human papilloma virus ) VIRUSES

13. Mobile genetic elements that infect bacteria Indirectly cause human diseases Encodes virulence factor Exchange of these elements between bacteria Bacteriophages/ plasmids Converts Nonpathogens Pathogens Plasmids/ Transposons Encode antibiotic resistance Eg. Vancomycin – resistant enterococci BACTERIOPHAGE, PLASMIDS, TRANSPOSONS

14. Bacteria Prokaryotes – have cell membrane Gram positive - thick wall surrounding the cell membrane (stain violet ) Gram negative - thin cell wall sandwich between 2 phospholipidbilayer membranes ( stain red ) Lack Nuclei Most synthesize their own DNA/RNA Depend on host for Favorable Environment Intracellular or Extracellular

15. CHLAMYDIA, RICKETTSIAE, MYCOPLASMA Divide by binary fusion Mycoplasma Lack cell wall Mycoplasma are tiniest living organism Airborne transmission Binds surface epithelial cells in airway Chlamydia Lack metabolic capabilities (ATP) Chlamydia & Rickettsia Obligate intracellular organism Mulitply in vacuoles inside the cell

16. FUNGI PROTOZOA Eukaryotes – thick chitin walls & ergosterol membrane Most exhibit Thermal Dimorphism HEALTHY PERSONS Dermatophytes – skin Subcutaneous tissue abscess & granulomas IMMUNOCOMPROMISED Deep fungal infxn  invade tissues AIDS Lethal Pneumonia by Opportunistic Pneumocystiscarinii Single-celled eukaryotes Trichomonasvaginalis Intestinal protozoa Blood borne protozoa Plasmodium spp

17. HELMINTHS ECTOPARASITES Multicellular organism Life cycle Roundworms- Nematodes ASCARIS FILARIA/ TRICHINELLA Flatworms- Cestodes Tapeworms Flukes – Trematode Schistosoma Arthropods Lice Ticks Bedbugs Live on the skin May be vectors for other pathogens Lyme disease by ticks

18. TRANSMISSION & DISSEMINATION OF MICROBES ROUTES OF ENTRY Spread & Dissemination Release of Microbes Sexually Transmitted Infection

19. HOST BARRIERS TO INFECTION & ROUTES OF ENTRY

20. SKIN

21. GIT- Barrier

23. Low gastric acidity

24. Antibiotics

25. Stalled peristalsis

26. Organism develop strategies to overcome defenses

27. Nonenveloped viruses may resist digestive enzymes - HAV, Rotavirus

29. Respiratory Pathogens Influenza Virus (+) Hemagglutinin proteins on surface  bind sialic acid on epithelium of host  engulf by cell  virus replicate inside cell (+) Neuramidase Cleaves sialic acid – Allow viral release from cell Lowers the viscosity of the mucus  facilitates viral transit Staphyloccoci ( Secondary Infection ) Gain access to host cell after viral infxn cause loss of ciliated epithelium

30. UROGENITAL

31. Spread & Dissemination of Microbes

32. 1. Proliferate Locally at the site Adhere & Proliferate in/on Epithelial Cells HPV , Dematophytes Confined to Lumen of Hallow Viscera Cholera Spread & Dissemination of Microbes

33. Spread & Dissemination of Microbes 2. Penetrate the epithelial barrier  Spread via Hematogenous or Lymphatic or Nerve Invasiveness Due to: Motility Secrete Lytic enzymes- Hyaluronidase Degrades extracellular matrix between cells Strep & Staph Initial spread  Follow tissue Planes of Least Resistance  Regional LN  Blood Stream  Distant organs Abscess  Regional LNs  Bacteremia  Colonize distant organs

34. Spread & Dissemination of Microbes HEMATOGENOUS SPREAD FREE - Polio, HBV, fungi, protozoa W/in WBC – HSV, HIV, TB W/in RBC - Plasmodium Nerve

35. Spread & Dissemination of Microbes 3. Viral Propagation A). Propagate from Cell to Cell by replication B). Propagate By Fusion or Transport within Nerves – Rabies, VZV 4. Placental – Fetal Route Bacterial / MycoplasmaPlacentitis Premature delivery Maldevelopment - Rubella Severe in Early trimester Syphilis affect mother late in 2nd Trimester Passage to birth canal- Gonococcal, Chlamydia Maternal Milk – CMV, HBV, HTLV-1

36. Maternal transmission HIV – Major cause of AIDS in children HBV – Can later cause Chronic Hepatitis & Liver Ca Notes:

37. Release of Microbes from the Body Important in the Transmission

39. Respiratory Viruses & Bacteria Infectious only when lesions are open to AIRWAYS Fecal-oral Water-borne viruses HAV, HEV, Polio, Rotaviruses Saliva EBV, CMV, Mumps Larval penetration Hookworms, Schistosomiasis Transmission- Person to Person

40. Sexual / Prolonged Intimate or Mucosal Contact Viruses - HPV, HSV, HBV, HIV Bacteria – Syphilis, Gonorrhea, Chlamydia Protozoan – Trichomonas Candida Blood & Blood products/ Needle pricks, etc HBV, HCV, HIV Transmission- Person to Person

41. Direct Contact or Consumption of Animal products Indirectly via an Invertebrate vectors Insects, Ticks, Mites Transmission – Animals to HumanZOONOTIC INFECTIONS

42. SEXUALLY TRANSMITTED INFECTONS

44. Chlamydia & Neisseria – Usually by sexual intercourse

45. Shigella & Entamoeba – Occasionally spread by sex

46. High Risk Groups for STIAdolescent Men with Men Illegal drug user

48. Usually dependent on Direct person to person spread

49. Initial site of infection – urethra, vagina, rectum, oropharynx

50. Most are Asymptomatic carriersSTI

52. Risk factors are the same for all STI’s

53. Biologic interaction between them  Increase the spread of infxn

54. Gonococcalcervicitis  local tissue damage  Increased chance of HIV infxn

55. STI  Vertical Spread

56. C. trachomatis – conjunctivitis

58. VIRULENCE Ability of microbe to infect , colonize, damage host tissues HOST RESISTANCE Ability of host defense mechanisms to eradicate infection – Innate & Adaptive Immune Defenses Outcome of Infection – Determined

59. INNATE DEFENCES Physical Barriers Macrophages NK cells Plasma Proteins – Complement , Cytokines, Acute phase reactants Adaptive Immune response Are stimulated by exposure to microbes Increase in magnitude, speed & effectiveness with successive exposure Mediated by T & B lymphocytes and their products Immune Defenses

60. HOW MICROORGANISMS CAUSE DISEASE DIRECT LY CAUSE CELL DEATH TOXIN / ENZYME RELEASE INDUCE CELLULAR RESPONSES

61. MECHANISMS OF VIRAL INJURY

62. Tissue Tropism Predilection of virus to infect certain cells and not others. Tropism Determined : HOST CELL RECEPTOR- MAJOR DETERMINANT CELLULAR TRANSCRIPTION FACTORS That Recognize Viral Enhancer & Promoter Sequences Allow Viral replication inside the cell ANATOMIC BARRIER LOCAL TEMPERATURE pH HOST DEFENSE

63. 1. Binding to host cell surface proteins Viruses possess specific cell-surface PROTEINS Viruses may use Normal Cellular Receptors of Host Host Proteases are Needed  For Binding Host Proteases Cleaves & Activates Influenza Hemagglutinin 2. Translocation into cytosol 3. Replication via virus specific enzymes Viruses Enter Host (+) Hemagglutinin proteins on surface  bind sialic acid on epithelium of host  engulf by cell  virus replicate inside cell (+) Neuramidase– lowers the viscosity of the mucus  facilitates viral transit

64. Mechanism of Viral injury

65. Cytopathic Effects - Virus Kill Cell Directly

66. Inducing Host immune response to virus – infected cells Host (CTL) Lymphocytes attack virus-infected cells FAS Ligand on CTL binds FAS receptor in liver cells Eg. Hepatitis B virus Virus Damage Cell involved in Host Antimicrobial Defense  Secondary Infections Viral killing of one cell type cause the death of the other cells Motor denervation  atrophy of the muscles Antiviral Immune responses

67. 1. ABORTIVE 2. LATENT 3. PERSISTENT Viral Infection can be:

68. BACTERIAL INJURY TO HOST TISSUES Bacterial Virulence ADHERE TO HOST CELLS  ENTRY DELIVER TOXINS Virulence of Intracellular Bacteria

69. Mechanism of Bacterial Injury

70. Virulence genes Plasmids & Bacteriophage Mobile genetic elements Spread between bacteria Encode virulence factors – Abtic resistance, toxins Quorum sensing Induce expression of virulence factor as their concentration in tissues increases Eg. Staph aureus - abscess Biofilm formation Live in viscous layer of extracellular material Enhance adherance & Inaccesible IV catheters, Artificial joints Bacterial Virulence

71. Bacterial Adherence

72. Bacterial Adherence

73. Infect either Epithelial cells – Shigella, Invasive E. coli Macrophages – Mycobacteria Both – S. typhi Escape immune system- TB Facilitate spread Interact w/ cell Inhibit host CHON synthesis – Shigella & E.coli Blocks fusion of acidic lysosome to form phagosome – M.TB Virulence of Facultative Intracellular Bacteria

74. Some Mechanisms of Bacterial Entry to Cell

75. Some Mechanisms of Bacterial Entry to Cell

76. Inhibit host protein synthesis  Replicate rapidly  Lyze host cell w/in 6 hours Blocks fusion of lysosome with phagosome  allow bacteria to replicate unchecked w/in macrophages Effect of Bacteria inside the cell

77. Bacterial Toxins

78. Lipopolysaccharides Large outer cell wall of gram negative Response of Host Beneficial Detrimental ENDOTOXINS

79. Lipopolysaccharide- Beneficial EffectActivates immune response

80. Lipopolysaccharide-Harmful Effect

81. Exotoxin- Secreted proteins 1. ENZYME - Protease staph. Split epidermis from dermis 2. TOXINS – with A-B toxins A subunit – enzymatic activity INACTIVATES HOST PROTEINS – Cholera/Diptheria DEGRADES HOST PROTEINS - Botulinum B-subunit – binding receptor & delivers A subunit to the cell

82. 3. Neurotoxins – Clostridium botulinum & tetani Inhibit release of neurotransmitters But do not kill neurons 4. Superantigens – staph aureus, strep pyogenes Stimulate very large T-lymphos Lead to very high lymphocyte proliferation and cytokine release  Capillary leak  shock Exotoxin

83. INJURIOUS EFFECTS OF HOST IMMUNITY

84. TB  Granulomatous inflammation ( Delayed Hypersensitivity Reaction ) Prevents spread of microbe But cause tissue Damage & Fibrosis HepaB Immune response  Liver damage Beta hemolytic Strep  Ab against M protein  Cross react w/ cardiac proteins  RHD  Ag + ASO (anti streptococcal antibodies)  Deposit in renal glomeruli causing  PoststreptococcalGlomerulonephritis Immune response  Tissue injury

85. IMMUNE EVASION BY MICROBES

86. Remaining inaccessible to host immune response Varying or shedding antigens Resisting innate immune defenses Preventing T-cell activation Impairing effective T-cell antimicrobial responses by specific or non-specific immunosuppression Mechanism of Immune evasion by Microbes

88. Propagate in the lumen of Intestine – Clostridium difficile Gallbladder – Salmonella typi Shed from luminal surface of epithelial cells CMV- urine, milk Polio – stool Infect the keratinized skin – Pox virus Infect Host cell – malaria Encyst in tissues – tapeworms Viral Latency – many viral genes are not expressed Inaccessible to Host Immune

89. Varying antigens / Shedding antigens Low fidelity of Viral RNA polymerases HIV Reassortment of viral genomes Influenza virus Different capsular polysaccharides Strep Pneumoniae Shed antigens w/in minutes of penetrating the skin Preventing recognition by antibodies Schistosomamansoni

90. Resisting Innate Immune Response CAMP Resistance Cationic antimicrobial peptides ( CAMP ) Defensin, Cathelicidins Initial defense against invading microbes Enabling them to avoid killing by pmns & macropahges Carbohydrate Capsule Pneumococcus, Meningococcus, Hemophilus PREVENTI PHAGOCYTOSIS K1 capsule containing sialic acid E. coli- meningitis Sialic acid will not bind C3b ( alternate complement pathway)

91. Covering them with host proteins Staph aureus covered by A molecules that bind Fc portion inhibit Phagocytosis Protease Degrade antibodies Neisseria, Hemophilus, Streptococcus Replicating w/in phagocytic cells Mycobacterium, cryptococcus Resisting Innate Immune Response

92. Some viruses block complement activation HERPESVIRUSES, POXVIRUS Produce homologues of IFN/ IFN receptors INHIBIT THE ACTION OF SECRETED IFN Produce cytokine mimics EBV – homologue of IL 10 ( Bind & Inhibit secreted IFN ) Resisting Innate Immune Response

93. Decrease Recognition of Infected cells by CD4 , CD8

94. Decrease Recognition of Infected cells

95. Decrease Recognition of Infected cells

96. Immunosuppression