Bacterial Pathogenesis Flashcards

Overview of Bacterial Pathogenesis

  • Definition of Pathogenesis: The specific processes used by pathogens to produce a disease state.

  • Fundamental Mechanisms of Bacterial Pathogens:     * Attachment: Utilizing mechanisms to adhere to various host surfaces and tissues.     * Nutrient Acquisition: Damaging host tissues to obtain essential nutrients and facilitate replication.     * Immune Evasion: Developing methods to avoid or subvert the host immune responses.

  • Virulence Factors: Defined as pathogen products (molecules or structures) that enhance the ability of the microbe to cause disease.

Bacterial Attachment Factors

  • Introduction to Attachment: Attachment factors are typically the first virulence factors a host encounters during an infection.

  • Fibronectin-binding Proteins:     * Fibronectin: A large plasma glycoprotein found in the plasma and extracellular matrix.     * Significance: Because it is ubiquitous throughout the human body, it serves as a primary target for pathogen binding.

  • Fimbriae:     * Structure: Specialized pili characterized by having an adhesive tip.     * Function: Acts as a "probe" to extend beyond the repulsing negative charge of the host cell.     * Immune Evasion: Some microbes can alter the composition of fimbriae to evade host immunity.

  • Table 21.3: Pathogens Utilizing Fimbriae for Adherence:     * Bordetella pertussis: Targets ciliated epithelial cells of the upper respiratory tract; causes Pertussis (whooping cough).     * Corynebacterium diphtheriae: Targets upper respiratory tract and skin epithelial cells; causes Diphtheria.     * Escherichia coli (Intestinal pathogenic strains): Targets intestinal cells; causes diarrhea and enteritis.     * Escherichia coli (Uropathogenic strains): Targets urinary epithelial cells; causes cystitis (bladder infection) and urethritis.     * Haemophilus influenzae: Targets sialic acid; causes meningitis and pneumonia.     * Klebsiella pneumoniae: Targets collagen; causes meningitis and pneumonia.     * Neisseria gonorrhoeae: Targets cervical and urethral epithelial cells; causes Gonorrhea.     * Pseudomonas aeruginosa: Targets GM1GM1 gangliosides; causes pneumonia and skin disease in compromised individuals.     * Salmonella Typhimurium: Targets various intestinal cells; causes gastroenteritis.     * Streptococcus agalactiae: Targets mucosal epithelial cells; causes neonatal meningitis.     * Streptococcus pneumoniae: Targets pharyngeal epithelial cells; causes pneumonia.     * Streptococcus pyogenes: Targets fibronectin and collagen; causes pharyngitis, tonsillitis, and invasive skin diseases.     * Vibrio cholerae: Targets intestinal microvilli; causes Cholera.

Specialized Adherence Proteins and Capsules

  • Tir and Intimin (Pathogenic E. coli):     * Mechanism: Intimin on the E. coli cell interacts with Tir (Translocated intimin receptor) on intestinal cells.     * Injection: Tir is produced by the bacteria and injected into the host intestinal cells via a Bacterial Type III Secretion System (T3SS).     * Pedestal Formation: The interaction between Tir and Intimin produces a "pedestal" structure from the intestinal cells, allowing the bacteria to latch on and obtain nutrients.

  • Capsules:     * Structure: An extracellular, loose matrix composed of polysaccharides.     * Virulence Functions:         1. Blocks opsonization, thereby interfering with phagocytosis.         2. Blocks the binding of antibodies and complement proteins.         3. Reduces entry into the endocytic pathway, which lessens antigen presentation.         4. Mimics "self" molecules to prevent the stimulation of host immune responses.

  • Table 21.4: Major Pathogens Possessing Capsules:     * Bacillus anthracis: Poly-D-glutamic acid capsule; causes Anthrax.     * Campylobacter jejuni: Various polysaccharides; causes invasive intestinal disease.     * Enterococcus faecalis: Various polysaccharides; causes UTIs and hospital-acquired diseases.     * Escherichia coli K1: Sialic acid capsule; causes neonatal meningitis.     * Haemophilus influenzae: Six types; one is polyribitol phosphate; causes pneumonia and meningitis.     * Klebsiella pneumoniae: Over 7777 different polysaccharide types; causes pneumonia and meningitis.     * Neisseria meningitidis: Sialic acid capsule; causes meningitis.     * Pseudomonas aeruginosa: Alginate (assists in biofilm formation); causes pneumonia.     * Salmonella Typhi: N-acetylglucosamine uronic acid; causes Typhoid fever.     * Staphylococcus aureus: Various amino sugars; causes skin diseases and pneumonia.     * Streptococcus agalactiae: Sialic acid capsule; causes neonatal meningitis.     * Streptococcus pneumoniae: Over 9090 different oligosaccharide types; causes meningitis and pneumonia.     * Streptococcus pyogenes: Hyaluronic acid capsule; causes invasive and toxic infections.

Methods for Releasing Virulence Factors

  • Table 21.5: Release Mechanisms and Associated Toxins:     * Cell Lysis: Streptococcus pneumoniae (Pneumolysin).     * Secretion to Environment:         * Clostridium tetani (Tetanus toxin).         * Clostridium botulinum (Botulinum toxin).         * Gram-negative species (Lipopolysaccharide).         * Shigella dysenteriae and E. coli O157:H7 (Shiga toxins).         * Streptococcus pyogenes (Streptolysin O; superantigens).         * Staphylococcus aureus (Alpha-toxin; superantigens).         * Vibrio cholerae (Cholera toxin).         * Bordetella pertussis (Pertussis toxin).         * Helicobacter pylori (VacA).         * Listeria monocytogenes (Listeriolysin).     * Injection into Host Cell:         * E. coli (EHEC/EPEC): Tir.         * Salmonella Typhimurium: SipA, SopE (prevent phagolysosome fusion).         * Pseudomonas aeruginosa: Exoenzyme S and U.         * Helicobacter pylori: CagA.         * Agrobacterium tumefaciens: Ti plasmid, VirE2, VirD2.

  • Type III Secretion Systems (T3SS):     * Salmonella Typhimurium uses two different T3SSs.     * Factors are injected to induce pseudopodia for bacterial uptake and to prevent the fusion of the phagosome with lysosomes.     * Death of intestinal cells/macrophages occurs via apoptosis, spreading the infection.

Iron-binding Proteins and Microbes in Focus

  • Importance of Iron: Iron is a strictly limiting nutrient for pathogens; they must compete with the host to obtain it.

  • Strategies for Obtaining Iron:     * Siderophores: Molecules that bind iron with high affinity, competing directly with host iron-binding proteins.     * Bacterial Transport Proteins: Proteins that bind host iron-binding proteins to "steal" the iron.     * Lowering pH: Pathogens lower the pH at the infection site to impair host iron-binding protein activity.     * Hemolysins: Production of cytolysins to lyse host cells and access internal iron stores.

  • Mycobacterium tuberculosis and the "White Plague":     * Tuberculosis (TB) is caused by M. tuberculosis, which requires iron for survival.     * Historical Context: Known as "the white plague" due to symptoms like physical wasting, pale skin, weakness, and hemoptysis (coughing up blood).     * Cytokine Link: Symptoms are caused by the inflammatory cytokine TNF-alpha (TNF−αTNF-\alpha).     * Mythology: TB symptoms were historically associated with the myth of vampirism.     * Fashion: The "weak and vulnerable" look of TB was considered fashionable between the 1930s and 1950s.

Bacterial Toxins: Endotoxins and Exotoxins

  • Inflammation Induction: Both superantigens and endotoxins can induce inflammation individually; together, they act synergistically to cause shock and death.

  • Endotoxins (Part of cell wall):     * Lipopolysaccharide (LPS): Primary endotoxin of Gram-negative bacteria.         * Three Components: O-antigen, Core polysaccharide, and Lipid A (the inflammatory portion).     * Lipiteichoic Acid (LTA): Found in Gram-positive cells; similar to LPS, recognized by TLRs, and induces inflammation.

  • Table 21.6: Biological Effects of Endotoxin/LTA:     * Fever: Inhibits pathogen replication.     * Complement Activation: Lysis by Membrane Attack Complex (MAC).     * Inflammation: Transports immune cells to the infection site.     * B-cell Proliferation: Leads to antibody production.     * IFN-gamma Expression: Activates macrophages and Natural Killer (NK) cells.     * Clotting Cascade: Prevents the spread of the pathogen.

  • Exotoxins (Released from the cell):     * A-B Toxins: Composed of a B subunit (binds to host receptor) and an A subunit (enzymatic activity inside the cell).     * Cytolysins: Act directly on host cell plasma membranes.     * Superantigens: Nonspecifically stimulate T cells to secrete massive amounts of cytokines.

Detailed Mechanisms of A-B Toxins

  • Diphtheria Toxin (Corynebacterium diphtheriae):     * Mechanism: B subunit binds the receptor; endosome acidification causes a conformational change, releasing the A subunit into the cytoplasm.     * Action: ADP-ribosylation of EF2 (elongation factor 2), halting protein synthesis.     * Clinical: Causes a "pseudomembrane" (fibrous lesion) in the pharynx. The toxin is encoded by a temperate phage.     * C. diphtheriae Description: Gram-positive, non-motile, non-endospore-forming rod (2−6 μm2-6\,\mu m). Appears like "Chinese script" or cuneiform.

  • Neurotoxins (Action on SNARE proteins):     * SNARE Proteins: Used by host cells to release neurotransmitters via vesicle fusion.     * Botulinum Toxin (Clostridium botulinum): Cleaves SNAP-25; prevents the release of acetylcholine causing flaccid paralysis (prevents contraction).     * Tetanus Toxin (Clostridium tetani): Cleaves synaptobrevin in inhibitory neurons; prevents the release of glycine and GABA (gamma-aminobutyric acid). Results in continuous muscle contraction (lockjaw).

  • Other A-B Toxins (Table 21.7):     * Cholera Toxin (Vibrio cholerae): ADP-ribosylation of GsG_s protein; increases cAMP levels, disrupting cellular ion/water flow (severe diarrhea).     * Pertussis Toxin (Bordetella pertussis): ADP-ribosylation of GiG_i protein; increases cAMP levels in respiratory ciliated cells.     * Shiga Toxins: Cleaves host ribosomal RNA (rRNArRNA); inhibits protein synthesis. Associated with Hemolytic Uremic Syndrome (HUS).

Bacterial Toxins: Cytolysins and Superantigens

  • Cytolysins: Deteriorate plasma membranes by forming pores or degrading phospholipids.     * Hemolysins: Lyse red blood cells; lysis patterns are used for bacterial identification.     * Lecithinase (Alpha-toxin): C. perfringens toxin that degrades membrane lipids (Gas gangrene).     * Listeriolysin: L. monocytogenes toxin; forms pores in the acidic environment of the phagosome, allowing the pathogen to escape into the cytoplasm.     * STAPH Alpha-hemolysin (S. aureus): Monomers oligomerize to form a pore. Small pores allow calcium influx, inducing apoptosis.     * PV Leukocidin (S. aureus): Targets phagocytes; damages mitochondrial membranes to induce apoptosis.

  • Superantigens:     * Action: Act on helper T cells (CD4+CD4^+) by stimulating them without specific antigen recognition.     * Consequence: Massive release of nonspecific cytokines, resulting in systemic inflammation, shock, and death.     * Toxic Shock Syndrome (TSS): Associated with super-absorbent tampons (e.g., Rely tampons) and polyacrylate; cases dropped after withdrawal from market.     * Food Poisoning: Enterotoxins from S. aureus are superantigens. They are heat-stable; underheating kills the bacteria but not the toxin.

Pathogen Study 1: Streptococcus pyogenes

  • General Features: Opportunistic pathogen with numerous virulence factors.

  • Diseases (Table 21.10): Pharyngitis, Tonsillitis, Cellulitis, Erysipelas (dermis infection), Impetigo, Scarlet Fever (caused by erythrogenic toxins SPE A, B, C), Necrotizing Fasciitis, and Septicemia.

  • Post-Streptococcal Sequelae:     * Glomerulonephritis: Post-infection kidney damage thought to involve immune complex deposition.     * Rheumatic Heart Disease: Result of cross-reactivity where antibodies against the bacterial M5 protein attack similar amino acid sequences in heart myosin.

  • Virulence Factors (Table 21.11):     * M Protein: Binds antibodies by the FcFc region (inverted orientation) to prevent opsonization; binds serum factor H to discourage complement.     * Hyaluronic Acid Capsule: Acts as a "self" mimic to prevent immune recognition.     * C5a Peptidase: Degrades complement factor C5a to prevent phagocyte migration.     * Streptokinase: Dissolves fibrin clots to facilitate spread.     * SIC (Streptococcal inhibitor of complement): Prevents/disassembles the MAC.

Pathogen Study 2: Mycobacterium tuberculosis

  • Cell Wall: Contains unique mycolic acids; requires acid-fast staining.

  • Access/Infection: Spread via aerosols; replicates inside lung macrophages.

  • Co-opting the Immune System: The bacteria encourage phagocytosis via opsonization with C3b and mannose-binding lectin (MBL).

  • Survival Mechanisms:     * Prevents phagosome-lysosome fusion.     * Lipoarabinomannan (LAM): A cell wall component that downregulates the oxidative burst and neutralizes toxic oxygen species.     * Produces Superoxide Dismutase and Catalase.

  • Disease Consequences:     * Granulomas: Chronic elevated TNF−αTNF-\alpha leads to walled-off lesions that damage lung tissue.     * Caseous Necrosis: Occurs when granulomas "crack open," releasing the microbe and toxic compounds, creating a pale, cheese-like lung consistency.

  • Tuberculin Skin Test: Injection of solubilized proteins. A positive result is a raised induration of 10−15 mm10-15\,mm appearing in  72~72 hours.

Evolution of Bacterial Pathogens

  • Horizontal Gene Transfer (HGT): Allows "evolution by quantum leaps" rather than slow mutation.     * Mechanisms: Conjugation, Transposable elements, Plasmids (Transformation), and Temperate (Lysogenic) phages.

  • Pathogenicity Islands: Large DNA stretches found in pathogenic strains but absent in non-pathogenic ones.     * Features: Unusually high or low G+C content; flanked by direct repeats; adjacent to tRNA genes; contain mobile genetic elements.

  • Phage Transduction Examples: C. diphtheriae, E. coli O157:H7, and V. cholerae.

  • The Toxin-Iron Connection: The diphtheria toxin gene and a siderophore gene are both under negative control by iron. When iron is low (as in the human body), the phage-encoded toxin is expressed to help provide nutrients to the bacterial "vehicle."

  • Protozoa as "Prep School": Many pathogens (e.g., Legionella pneumophila) evolve by surviving inside amoebae in the natural environment. This prepares them to exploit similar eukaryotic cells, such as human lung cells.

Questions & Discussion

  • Q: Why would a phage carry a toxin gene against a eukaryotic cell?     * A: It is likely in the phage's best interest to support its host (the bacterial cell). Since iron is low in the human host, and the toxin genes are repressed by iron, the expression of toxins during infection helps the bacterial cell obtain the nutrients it needs to thrive, which in turn facilitates the phage's survival.

  • Q: How does the Tuberculin skin test work?     * A: Solubilized proteins are injected under the skin. If the individual was previously exposed, a cell-mediated immune reaction occurs, creating an induration. It may not show positive in the immunocompromised or if the infection is very recent. Follow-up usually involves chest X-rays to look for granulomas.

  • Q: What is the relationship between Toxic Shock Syndrome and tampons?     * A: Super-absorbent tampons, particularly those containing polyacrylate (like Rely tampons), were associated with a surge in TSS cases in the late 1970s and early 1980s. Removing these materials from the market led to a significant decrease in cases.