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

 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

 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

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

Disease Health Disease Health  Disease Health 

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

 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

 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

Adhesins bind to specific receptors on host cells

 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)

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!

 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

 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

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 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

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Diphteria Membrane

 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

*phage coded

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

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

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

 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

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

 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

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

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

 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

 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

  oflagellates.html oflagellates.html  Primary Literature available on request