1. Host-Pathogen Relationships • Pathogenic organism (= parasitic) • a symbiont that harms or lives at the expense of its host

2. Pathogenicity and disease • infection • growth and multiplication of parasite on or within host • infectious disease • disease resulting from infection • pathogen • any parasitic organism that causes infectious disease • primary (frank) pathogen – causes disease by direct interaction with host • opportunistic pathogen – causes disease only under certain circumstances • pathogenicity • ability of parasite to cause disease

3. Steps in an infectious disease 1. Encounter 2. Entry 3. Spread 4. Multiplication 5. Damage 6. Outcome

4. Mechanisms of bacterial pathogenesis 1. Enter 2. Stay 3. Eat 4. Evade defenses

5. Normal Microbial Flora Normal flora - microbes frequently found on or within the bodies of healthy persons commensal organisms Members of the normal flora bacteria - vast majority viruses fungi protozoa Colonization by bacteria occurs rapidly after birth. Thousands of bacterial species are part of the normal flora.

6. Locations in body with largest amounts of bacteria skin respiratory tract digestive tract urinary tract genital system Other body locations have small numbers of bacteria. Some body locations are sterile. Transient vs. resident organisms Pathogenicity/virulence also depend on the host

7. Role of normal flora keeping out pathogens immune stimulation assist in nutrition source of carcinogens source of infection

8. Exampleswhere normal flora are source of infection: periodontitis - overgrowth of particular bacteria in gingival crevices pneumonia - defenses lowered and microaspirations of pneumococci. catheter-associated infections - staphylococci

9. Mechanisms of bacterial pathogenesis 1. Enter 2. Stay 3. Eat 4. Evade defenses

10. Enter ingress versus penetration

11. 2. Stay A. Surface colonization Preference of bacteria for particular locations in body bacteria vary in specificity tissue tropism Adhesins on surface of bacterium Receptors on surface of host cell Examples: gram-negative bacteria fimbriae pili interact with host glycolipids invasins on bacterial cell surface interact with host integrins gram-positive bacteria often bind host fibronectin (epithelial cells)

12. fimbriae E. coli

13. 2. Stay B. Biofilm formation C. Invasion through mucosa or into cells

14. 3. Eat Finding a nutritionally compatible niche Intermittent availability of food for some bacteria e.g. intestinal bacteria Adaptation to particular location

15. 4.Surviving host defenses A. Defending against complement masking and inhibition B. Subverting phagocytosis inhibiting phagocyte recruitment and function killing phagocytes escaping ingestion surviving inside phagocytes C. Subverting immune responses superantigens (diverting lymphocyte function) changing antigenic coats proteolysis of antibodies

16. (5. Transmission to a new host) A. passive transmission B. active transmission transit forms effects on host

17. Damage by Microbial Agents 1. Host cell death Lysis of host cells Apoptosis (programmed cell death) 2. Alteration of the metabolism of host cells caused by toxins 3. Damage due to host responses Inflammation (obstruction) Immune response

18. Toxins Microbial product or component that can injure another cell or organism at low concentrations Exotoxins secreted by pathogens or expressed on cell surface Endotoxins lipopolysaccharides of the outer membrane of gram-negative bacteria

19. Mechanism of exotoxin action Toxins that act outside of host cells A. help microbes spread B. lyse cells lipases pore proteins 2. Toxins that act inside of host cells A. block protein synthesis (kills) B. elevate/depress cell functions includes neurotoxins

20. Common features of toxins that act inside of host cells A-B toxins (2 components) Require activation Many are ADP-ribosyltransferases NAD

23. Protection against exotoxins A. Immunization with toxoids B. Treatment with antitoxins “passive immunization”

24. Endotoxin LPS Active toxin part = Lipid A

25. Effects of endotoxin • Alarm reactions (low concentration) a. Fever b. activation of complement c. activation of macrophages d. Stimulation of B lymphocytes • Shock a. hypotension b. disseminated intravascular coagulation (DIC)

26. Virulence factor - any component of a pathogenic microbe that is required for or that potentiates its ability to cause disease

27. Transfer of genes encoding virulence factors Transformation - naked DNA transferred into a cell (no cell to cell contact) Transduction - DNA transferred into a cell by a virus (bacterial virus = bacteriophage) Conjugation - DNA directly transferred from one cell to another cell (cell to cell contact)

28. Fate of DNA in recipient cell maintained as an episome (separate from the bacterial chromosome) integrated into chromosome by recombination reciprocal recombination (transformation) (homologous) site-specific recombination (phage DNA) (nonhomologous) replicative recombination (transposons) (nonhomologous)

29. Lysogenic phages and bacterial pathogenesis Many examples of prophages carrying genes for virulence factors Pathogenic E. coli Prophages encode Shiga toxins f361 encodes Shiga toxin 2

30. Cornyebactrium diphtheria agent of diphtheria gene for diphtheria toxin (tox) carried on b prophage a bacterial chromosomal gene regulates tox expression Vibrio cholera agent of cholera CTXf carries genes for cholera toxin a bacterial chromosomal gene regulates toxin expression

31. Pathogenicity Islands • large segments of DNA that carry virulence genes • acquired during evolution of pathogen by horizontal gene transfer

32. Pathogenicity islands Phage-like characteristics Phage integrase gene near one end Small repeats at the ends (5-20 bp) as if created by site-specific recombination Staphylococcus aureus SaP11 pathogenicity island movement from cell to cell dependent on phage 80a Often pathogenicity islands encode components of a protein secretion system

33. Gram negative bacteria secretion systems Type I - ABC transporters Type II - two-step system Type III - contact dependent system Type IV - conjugal transfer system