Meeting 6 Disease Manifestations Virulence Factors Antimicrobial resistance

1. Meeting 6Disease ManifestationsVirulence FactorsAntimicrobial resistance 1 Aug 2009

2. Manifestations of infectious disease • Classic • Signs • Fever, swelling, rashes, vomiting, diarrhea • Skin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscess • Symptoms • Pain, headache, nausea, malais • Inflammation • Result of Immune reactions • Hematologic ( leukocytosis, anemia ) • Cardiac (tachycardia to heart failure) • Respiratory (hyperventilation) • Renal • Hepatic • Upper GI bleeding

3. Manifestations of infectious disease • Classic • Signs • Fever, swelling, rashes, vomiting, diarrhea • Skin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscess • Symptoms • Pain, headache, nausea, malaise • Inflammation

4. Flat lesion • MACULE • A macule is a change in the color of the skin. It is flat, if you were to close your eyes and run your fingers over the surface of a purely macular lesion, you could not detect it. A macule greater than 1 cm. may be referred to as a patch.

5. Elevated lesion • PAPULE • is a solid raised lesion that has distinct borders and is less than 1 cm in diameter. Papules may have a variety of shapes in profile (domed, flat-topped, umbilicated) and may be associated with secondary features such as crusts or scales.

6. Elevated lesion • TUMOR • is a solid mass of the skin or subcutaneous tissue; it is larger than a nodule.

7. Elevated lesion • PAPULE • is a solid raised lesion that has distinct borders and is less than 1 cm in diameter. Papules may have a variety of shapes in profile (domed, flat-topped, umbilicated) and may be associated with secondary features such as crusts or scales.

8. Depressed lesion • ATROPHY • Atrophy is thinning or absence of the epidermis or subcutaneous fat.

9. Depressed lesion • EROSION • Erosions are slightly depressed areas of skin in which part or all of the epidermis has been lost

10. Depressed lesion • ULCERATION • occur when there is necrosis of the epidermis and dermis and sometimes of the underlying subcutaneous tissue.

11. FEVER • 1. Fever increases the environmental temperature above the optimum growth temperature for many microorganisms. If the microorganisms are growing more slowly, the body's defenses have a better chance of removing them all. • 2. Fever leads to the production ofheat shock proteins that are recognized by some intraepithelial T-lymphocytes (delta gamma T-cells) resulting in the production of inflammation-promoting cytokines. • 3. Fever elevates the temperature of the body increasing the rate of enzyme reactions, and speeding up metabolism within the body. • can increase the production and activity of phagocytes, • speed up the multiplication of lymphocytes, • increase the rate of antibody and cytokine production, • increase the rate at which leukocytes are released from the bone marrow into the bloodstream, and speed up tissue repair. Too high of a body temperature, however, may cause damage by denaturing the body's enzymes.

12. FEVER • Fever may have certain signs in relation to its course. • Fever in infectious diseases usually is of short duration • Long duration (weeks or months) is always a very serious problem. If it is not possible to determine the cause of fever at the beginning, it is called the fever of unknown origin (FUO). This term is used to describe fever lasting at least 2 weeks, reaching temperatures above 38,2 , and the cause of the origin is uncertain. • Fever may last long in some infections with subacute or chronic course.

13. Stages in the Progression of Disease • No signs or symptoms • Prodormal illness • Mild signs or symptoms • Some chilling occur • Acute identifiable signs and symptoms • Intermittent fever • Recovery • Action of immune system • Action of antibiotics • Convalescence

14. Stages in the Progression of Disease

17. Manifestations of infectious disease • Result of Immune reactions • Hematologic ( leukocytosis, anemia ) • Cardiac (tachycardia to heart failure) • Respiratory (hyperventilation) • Renal • Hepatic • Upper GI bleeding

18. Case study 1 • S. T. was seen by you in the Emergency Room in December • 23 y/o medical student in Southern California • c/o sudden onset of fever, chills, malaise, headache, myalgia, sore throat, runny nose, sneezing • Room-mate has same symptoms • Exam: erythematous, inflammed tonsils, • no pharyngeal exudates • Throat culture: Group A streptococci

19. Case study 1 erythematous, inflammed tonsils

20. Case study 2 • P. A. is a patient in the Intensive Care Unit • 65 y/o man • Intubated, on respirator: good oxygenation • Nurse says that he hasn’t had fever or purulent sputum • Exam: clear breath sounds, no rhonchi nor rales • CXR: clear without infiltrates or effusions • Sputum Gram stain: mixed flora with Gram positive cocci; thin, long Gram negative rods • Sputum culture: normal respiratory flora, 2+ Pseudomonas aeruginosa

21. Case study 3 • T. M. was referred to you by the Public Health Department • 38 y/o woman • Private cook in Manhattan • In the past 10 years, 7 of the 8 families she has worked for have had outbreaks of illness: • Fever, malaise, headache, myalgia, maculopapular rash, bradycardia, constipation, bloody diarrhea • T. M. denies h/o similar illness and denies current symptoms • “But, Doctor, I’m not sick!”

22. Case study 3 maculopapular rash

23. Disease state: complex interaction between pathogen and host • 1. If a bacterium is present, is it causing disease? • a. Normal flora • b. Colonization • c. Carrier state • d. Infection: • i. Asymptomatic • ii. Symptomatic • 2. Is the bacterium capable of causing disease? • a. Nonpathogen • b. Opportunistic pathogen • c. Primary pathogen

24. Case study 1: Viral pharyngitis + Group A strep normal respiratory flora • S. T. was seen by you in the Emergency Room in December • 23 y/o medical student in Southern California • c/o sudden onset of fever, chills, malaise, headache, myalgia, sore throat, runny nose, sneezing • Room-mate has same symptoms • Exam: erythematous, inflammed tonsils, • no pharyngeal exudates • Throat culture: Group A streptococci

25. Case study 2: Colonization with Pseudomonas aeruginosa • P. A. is a patient in the Intensive Care Unit • 65 y/o man • Intubated, on respirator: good oxygenation • Nurse says that he hasn’t had fever or purulent sputum • Exam: clear breath sounds, no rhonchi nor rales • CXR: clear without infiltrates or effusions • Sputum Gram stain: mixed flora with Gram positive cocci; thin, long Gram negative rods • Sputum culture: normal respiratory flora, 2+ Pseudomonas aeruginosa

26. Case study 3: Typhoid MarySalmonella typhi carrier • T. M. was referred to you by the Public Health Department • 38 y/o woman • Private cook in Manhattan • In the past 10 years, 7 of the 8 families she has worked for have had outbreaks of illness: • Fever, malaise, headache, myalgia, maculopapular rash, bradycardia, constipation, bloody diarrhea • T. M. denies h/o similar illness and denies current symptoms • “But, Doctor, I’m not sick!”

27. Outbreak 2001

30. Virulence Factors that Promote Colonization and Invasion • Virulence factors that damage the host • Exotoxins • Endotoxins • Ability to resist innate immunity • Ability to evade adaptive immunity • Ability to induce autoimmune response

31. Virulence Factors that Promote Colonization and Invasion • Basic requirements: receptor + adhesin • Receptor • Specific carbohydrate or peptide residues on the cell surface • Adhesin or adherence factor • A macromolecular component of the bacterial cell surface interacting to the receptor

32. Virulence Factors that Promote Colonization and Invasion • Surface proteins called adhesins in the bacterial cell wall bind to receptor molecules on the surface of a susceptible host cell enabling the bacterium to make intimate contact with the host cell, adhere, colonize, and resist flushing.

33. Virulence Factors that Promote Colonization and Invasion • Specific adherence of bacteria to cell and tissue surfaces • Tissue tropism • Strep mutansin dental plaque but not in the tongue • Species specificity • Neisseriagonorrheaelimited to humans • Genetic specificity within a species • Mechanism of specific adherence • Reversible attachment – “docking” • Non-reversible attachment – “anchoring”

34. Virulence Factors that Promote Colonization and Invasion: Example (Tabulate according to the ff: Bacterium:AdherenceFactor:Receptor(optional):Attachment Site: Disease) • Streptococcus pyogenes: • Protein F • Aminoterminus of fibronectin • Pharyngeal Epithelium • Sore Throat

35. S. pyogenes F-protein lipoteichoic acid fibronectin

36. Virulence Factors that Promote Colonization and Invasion: • Fimbriae • Adhesins • Protein F • Capsules • Invasins • Cleaves secretoryIgA (Glycosyltransferase) • Spreading factors: • Hyaluronidase – attacks the interstitial cement of connective tissue by depolymerizinghyaluronic acid • Collagenase • Neuraminidase • Streptokinase and staphylokinase • Siderophores • Low molecular weight compounds that chelate iron with very high affinity • Competing for iron and other nutrients

37. Virulence Factors that Promote Colonization and Invasion

38. Virulence Factors that Promote Colonization and Invasion

39. Virulence Factors that Promote Colonization and Invasion Glycocalyx • Polysaccharide or peptide slime • Capsule • Slime layer • Functions: • Resists phagocytosis • Enhanced attachment

40. Shigella Passing Through the Mucous Membraneand Invading Mucosal Epithelial Cells Virulence Factors that Promote Colonization and Invasion

41. Virulence Factors that Promote Damage to the Host: EXOTOXINS • Properties • Secreted during exponential growth • Protein toxins • High biological activity • Exhibits specificity of action • Components • A = active • B = binding

42. A-B toxins Cell surface Active Binding A B

43. Binding and Entry of an A-B Toxin • A-B toxins consist of two parts, an A (active) component and a B (binding) component.The B component of the exotoxin binds to a receptor on the surface of a susceptible host cell.The exotoxin now enters the host cell, in this case by endocytosis, and causes harm by inactivating a host cell target protein through ADP-ribosylation.

44. Virulence Factors that Promote Damage to the Host: EXOTOXINS • Based on structure • A-B prototype • Botulinum toxin, diphtheria toxin, shiga toxin, tetanus toxin • Membrane disrupting toxin • Lacks A & B • Pore forming • Phospholipase • Superantigens

45. Superantigens • 1. Some exotoxins are superantigens • 2. Produced by bacteria and viruses • 3. Action: polyclonal stimulation of subset of lymphocytes to divide and produce cytokines • 4. Best known example: Staph Toxic Shock Syndrome Toxin-1 (TSST-1) • 5. Also Strep exotoxins • 6. Pyrogenic toxins cause fever (unlike other exotoxins)

46. Murray, P.R. et al. Medical Microbiology, 3rd edition, 1998, p. 156 2-subunit A-B exotoxinNeurotoxin: Clostridium botulinum

47. Botulism Exotoxin Blocking Acetylcholine Release • The botulism exotoxin binds to the presynaptic neuron and blocks its release of acetylcholine. This causes a flaccid paralysis, a weakening of the involved muscles.

48. Membrane damaging exotoxins • Proteases • Phospholipases • Detergent-like action

49. Virulence Factors that Promote Damage to the Host: EXOTOXINS • Based on modes of action • Breaks down cells • Alpha toxins, hemolysins, leukocidins • Enhance microbial spread • Spreading factors: hyaluronidase, mucinase etc • Interfere in cellular metabolism • Tetanus toxin, botulinum toxin

50. Virulence Factors that Promote Damage to the Host: EXOTOXINS • 3 ways this can contribute to the progression of disease: • Ingestion of preformed toxin • Colonization of wound or mucosal surface followed by exotoxin production • Colonization of wound followed by local exotoxin production