Microbiology

PATHOGENESIS OF BACTERIAL INFECTIONS

2 Major Mechanisms: INVASION and INFLAMMATION PRODUCTION of TOXINS INVASION and INFLAMMATION A. ENZYMES 1. Collagenase and Hyaluronidase - Degrade collagen and hyaluronic acid - Spread through subcutaneous tissue - Cause Cellulitis: infection of the subcutaneous tissue by Streptococcus pyogenes - Purulent area- bacterial infection 2. Coagulase - Found in Staphylococcus aureus - Accelerates formation of fibrin clot - Fibrinogen Fibrin - Protect bacteria from phagocytosis (to cause disease) - Walls off organism 3. IgA protease - Degrades IgA (Secretory) - Adheres to mucous membranes (protective) - Invade tissues and cause disease - Found in: o Neisseria gonorrheae o Haemophilus influenza (cause Upper Respiratory Tract Infection) o Streptococcus pneumonia 4. Leukocidins - Destroys neutrophilic leukocytes and macrophages B. VIRULENCE FACTORS - Limit phagocytosis Further invade Cause disease 1. Capsule - Polysaccharide ccps1 Med 2014 -

Dr. Domantay

Prevents adherence of phagocyte/macrophages Opsonization: Anticapsular antibodies Quellung Test: Capsular Swelling Test Present in: o Streptococcus pneumonia o Haemophilus influenza o Neisseria meningitides All three are causative agents of meningitis Capsules can serve as an antigen to produce an antibody Vaccines induce anticapsular antibodies

2. Cell Wall Proteins - Found in gram positive cocci - M protein (found in the cell wall): Group A streptococci (S.pyogenes) o Antiphagocytic - Protein A: S. aureus o Binds to IgG and prevents activation of complement TOXIN PRODUCTION - Exotoxins vs. Endotoxins EXOTOXINS - Found in certain species of both gram positive and gram negative bacteria - Secreted from the cell; elaborated outside of the cell - Chemically: Polypeptides - Genes on plasmid or bacteriophage - High toxicity (small amounts needed to produce a clinical effect) - Varied clinical effects and modes of action - Induces high titer antibodies called ANTITOXINS - Toxoids used as vaccines - Heat labile: Destroyed rapidly at 60C - Tetanus, botulism, diphtheria ENDOTOXINS - Found in the cell wall of gram negative bacteria - Not secreted from the cell - Chemically: Lipopolysaccharide - Gene found in bacterial chromosome - Low toxicity (more amounts needed to produce a clinical effect)

Microbiology
Exotoxins: Diphtheria Toxin - Produced by Corynebacterium diphtheria - Inhibits protein synthesis cause cell death - ADP ribosylation of elongation factor-2 (EF-2) (happens during the process of Translation) - Pseudomembrane formation in the throat - Myocarditis (complication) - *Cells in the URT die (Necrosis) dead cells together form PSEUDOMEMBRANE - Structure: o Fragment A: enzyme (catalyzes) EF2+NAD EF-2 ADP ribose + nicotinamide o Frament B: mediates transport of Fragment A into cells Tetanus Toxin - Produced by Clostridium tetani - Neurotoxin; prevents the release of inhibitory neurotransmitter GLYCINE - Excitatory neurons are unopposed - Manifests as muscle spasm and spastic paralysis - Tetanospasmin - Structures: o Heavy chain: Binds to gangliosides in membrane of neuron (facilitates entry) o Light chain: Protease; degrades protein responsible for the release of inhibiting neurotransmitter - Opisthotonus: state of a severe hyperextension and spasticity; bridging position; caused by spasm of the axial muscles along the spinal column. - Risus Sardonicus in tetanus: Face muscle spasm; sarcastic smile. ccps2 Med 2014 Fever and shock Mode of action: TNF and IL-1 Poorly antigenic No toxoids forme; no vaccine available Stable at 100C for 1 hour Meningococcemia, sepsis by gram negative rods

Dr. Domantay

Botulinum Toxin - Produced by Clostridium botulinum - Neurotoxin; block the release of Acetylcholine at synapse - Flaccid paralysis (adults can suffer from dysphagia) - 2 subunits: o Binds to receptors on neuron (facilitates entry) o Protease - Six serotypes (A-F) - *Food poisoning dysphagia - Terminal stage: Respiratory muscles affected Dyspnea Respiratory paralysis Clostridium difficile - Causes Pseudomembranous colitis - Exotoxin A: enterotoxin; causes watery diarrhea - Exotoxin B: cytotoxin.; damages colonic mucosa Pseudomembranes Clostridium perfringens - Causes gas gangrene - Toxin that produces 7 lethal factors; 5 enzymes - Alpha toxin (most dangerous): a lecithinase (degrade lecithin in cell membranes) - Destruction of cell membrane Necrosis Cell death - Others: Collagenase, Protease, Hyaluronidase, DNAse - Some are enterotoxins cause diarrhea Bacillus anthracis - Causes anthrax - 3 EXTOXINS: o Edema Factor Adenylate cyclase increase cAMP in the cell loss of chloride and water EDEMA (swelling) *Sodium loss (where Na goes, water follows)

Microbiology
o Lethal Factor Protease (degrades proteins) Cleaves a phosphokinase required for the signal transduction pathway that control cell growth Protective Antigen Forms pores in human cell membranes Pores: serve as passageways for other factors to enter Forms skin ulcers (Cutaneous anthrax) Pulmonary anthrax (directly to the lungs) GI Anthrax (cause diarrhea)

Dr. Domantay

Erythrogenic Toxin - Produced by S. pyogenes - Scarlet fever (prominent erythymatous rash) - Superantigen acting like TSST - DNA that codes for toxin resides on a temperate bacteriophage Heat Labile Enterotoxin - Found in E.coli: causes watery non-bloody diarrhea - Stimulates adenylate cyclase in the cells in the small intestines - Increase cAMP - B subunit: binds to receptor - A subunit: enters the cell - Genes are carried on plasmids Heat Stable Enterotoxin - Polypeptide - Not inactivated by boiling - Stimulated guanylate cyclase - Increase cGMP - Inhibit reabsorption of fluids - Cause diarrhea Verotoxin Produced by E.coli: O157:H7 serotype Causes bloody diarrhea From uncooked hamburger Cytotoxic effect on Vero (monkey) cell in culture Inactivate protein synthesis causes cell death Removes adenine from 28S rRNA Shiga-like toxin (Shigella dysenteriae)

TOXIC SHOCK SYNDROME TOXIN (TSST) - Caused by S. aureus and certain strains of S. pyogenes - Acts as a SUPERANTIGEN - Binds to surface of macropahges - Interacts with T-cells - Release of IL-1 and Il-2 (cytokines) - Manifest signs and symptoms of TSS - Mitogen: induces T-cells to multiply - *In shock, it causes hypotension and fever Staphylococcal Enterotoxin - Superantigen - Lymphoid cells lining the small intestines - Food poisoning - Causes vomiting and watery diarrhea - Cytokines stimulate vomiting center in the CNS Exfoliatin - Produced by S. aureus - Causes Scalded Skin Syndrome - Cleaves desmoglein (protein in desmosomes); part of epithelium have cells connected to each other by desmosomes; usually near the BM - Causes detachment of superficial layers of the skin - Also called Epidermolytic toxin; causes peeling ccps3 Med 2014

Other enterotoxins - Vibrio cholerae (Cholera) - Bacillus cereus (usually thrives in reheated fried rice) - Similar to heat labile toxin of E.coli Pertussis Toxin - Produced by Bordetella pertussis - Causes whooping cough - 2 effects: o Stimulate adenylate cyclase Edema in respiratory tract Cough

Microbiology
o Lymphocytosis Inability of lymphocytes to enter lymphoid tissue Normal: Lymphocytes should be 20-40% In whooping cough: approx. 98-99% lymphocytes are Causes inspiratory whoop

Dr. Domantay

ENDOTOXINS: 1. FEVER - Released by macrophages of endogenous pyrogen (IL-1) - Acts on the hypothalamic temperatureregulatory center 2. HYPOTENSION and SHOCK - Bradykinin- induced vasodilatation Decrease in BP - Increased vascular permeability - Dercreased peripheral resistance 3. DISSEMINATED INTRAVASCULAR COAGULATION (DIC) - Activation of Hageman Factor XII (and all other factors) - Thrombosis, petechial or purpuric rash due to bleeding - All factors will be used up (Consumptive Coagulopathy) Bleed to death - Tissue ischemia (blood clots obstruct blood flow) - Due to spontaneous bleeding Petechiae 4. ACTIVATION OF ALTERNATIVE PATHWAY - Complement cascade - Inflammation and tissue damage 5. ACTIVATION OF MACROPHAGES AND BLYMPHOCYTES - Increased phagocytic ability - Increased antibody production

ccps4 Med 2014