1. Lecture 8: Microbial mechanisms of pathogenicity Edith Porter, M.D. 1

2.  Important definitions  The infection cycle  Bacterial pathogenesis ▪ How bacteria enter and invade a host ▪ How bacteria circumvent host defenses ▪ How bacteria damage host cells  Pathogenic properties of viruses  Pathogenic properties of fungi, protozoa, and helminths 2

3.  Pathogenicity  The ability to cause disease  Virulence  The extent or degree of pathogenicity  Obligate pathogen (pathogen)  Causes disease in the healthy adult by means of specific pathogenic factors  Typically not part of the normal microbiota  Opportunist  Causes disease only in individuals with locally or systemically compromised immune function  Often part of the normal microbiota

4.  ID 50 : Infectious dose for 50% of the test population  LD 50 : Lethal dose for 50% of the test population

5. Disease Health Disease Health  Disease Health 

7.  Mucous membranes  Parenteral route  Skin Schistosoma mansoni Trematode (Fluke), with male and female worms, live in blood vessels Penetration through intact skin

9.  Respiratory tract  Coughing, sneezing  Gastrointestinal tract  Feces, saliva  Genitourinary tract  Urine, semen, vaginal secretions  Skin  Blood  Biting arthropods, needles/syringes Exit route is typically the same as entry route

10.  Entry  Adherence  Penetration  Enzyme and toxin production  Direct damage to host  Evasion of host defense  Resistance to uptake by phagocytes  Change of surface molecule expression  Latency (hiding in host cells)  Degradation of host defense molecules

11. Adhesins bind to specific receptors on host cells

12.  Neisseria gonorrhoeae initiates receptor mediated uptake by urethral or cervical epithelial cells  Salmonella typhimurium invades intestinal epithelial cells using their cell surface protein invasin (rearranges the cytoskeleton)

13. Coagulase Coagulates blood (S. aureus, thick pus) Kinases Streptokinase* Digest fibrin clots Hyaluronidase* Hydrolyses hyaluronic acid Collagenase Hydrolyzes collagen Facilitate tissue degradation and spreading * Therapeutic use!

14.  Toxin  Poisonous substance  Molecule that contributes to pathogenicity  Toxigenicity  Capacity of a microbe to produce toxin  Toxigenic strains: strains producing toxins  Toxicity  Ability to induce toxic reactions in host  Toxemia  Presence of toxin the host's blood  Toxoid  Inactivated toxin used in a vaccine  Antitoxin  Neutralizing antibodies against a specific toxin

16.  Secreted by the microbe  Act locally and in a distance  Typically proteins  AB toxins: inactivate essential cell functions  Membrane disrupting toxins  Toxins overstimulating immune system

17. 17

18.  Toxins with 2 sub units:  A: Active component, mediates toxicity  B: Binding component, guides toxin to the target cell  Example: Diptheria toxin ▪ Inhibits elongation factor II in ribosomes, inhibits protein synthesis ▪ 0.01 mg can kill a 200 lb person C. diphteriae

19.  http://www.sumanasinc.com/webcontent/ani mations/content/diphtheria.html 19

20. Diphteria Membrane

21.  Disrupt host cell plasma membrane  Depending on target:  Hemolysins: erythrocytes  Leukocidins: phagocytes  Some destroy also other cell types  Examples:  Pore forming ▪ S. aureus alpha toxin ▪ S. pyogenes streptolysin -O and -S  Enzymatic ▪ C. perfringens phospholipase C (Bhakdi et al) Gas Gangrene SLO-Pores

22. *phage coded

23.  LPS (lipopolysaccharide)  Component of outer membrane of gram- negative bacteria  Triggers fever!  Pyrogen

25.  Capsules  M-protein in Streptococci  Intracellular survival  Escape into cytoplasma ▪ Rickettsia  Resistance against antimicrobial factors ▪ M. tuberculosis with lipids

26. Trypanosoma Vary surface glycoprotein 1 of 1000 genes expressed at a time Genes randomly switched on and off Schistosoma Assume host molecules Shedding of surface N. gonorrhoeae Vary outer membrane protein (opa) Influenza virus Changes in spikes Undulating Membrane Trypanosome cruzi

27.  Microbial agent (virus) retreats in host cells  HIV in Lymphocytes  Herpes viridae in Nerve cells  Herpes simplex ▪ Fever blister  Varizella Zoster Virus ▪ Chicken pox ▪ Latency in dorsal root ganglion ▪ Recurrence: zoster in skin cells

28.  Many mucosal pathogens produce IgA- proteases  Degrade antibody type A

29.  Inclusion bodies  Cell rounding  Cell aggregation  Syncytium: multinucleated cells  Inactivation of host defense cells (HIV)  Down regulation of host defense  Transformation: loss of contact inhibition, uninhibited growth  Cancerogenic  oncogens Negri bodies in rabies Transformed cells in culture

30.  Chronic infections provoke an allergic response  Toxins  Ergot toxin: Claviceps, Hallucinations, LSD like, abortions  Aflatoxin: Primary liver cancer  Mycotoxin: amanitin, neurotoxin, death

31.  Presence of protozoa  Protozoan waste products and products released from damaged tissue may cause symptoms  Avoid host defenses by  Growing in phagocytes  Antigenic variation

32.  Helminth body mass can block host liquid movement  Ileus with Ascaris infection  Elephantiasis (Filaria infection blockage of lymph vessels) Filaria Adult Elephantiasis Can survive for 5 – 10 y

34.  Virulence determined by invading microorganism and host defense  Entry route is typically same as exit route  Main pathogenic factors:  Promote entry  Damage host ▪ Enzyme and toxin production ▪ Toxins often phage coded  Evasion of host defense  Disease is a combination of direct cell damage and host defense response

35.  http://www.doctorfungus.com/thefungi/Cryptococcus.htm  http://www.geo.ucalgary.ca/~macrae/palynology/dinoflagellates/din oflagellates.html http://www.geo.ucalgary.ca/~macrae/palynology/dinoflagellates/din oflagellates.html http://www.mikrobiologie.medizin.uni-mainz.de/de/index.html  Primary Literature available on request