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BIOL 444
Christine Dupont

BIOL444 – Microorganisms & Diseases Fall 2012 Set 05 – Respiratory Tract Infections URT/Upper Respiratory Tract Infections (Usually colonized) - Nose, throat & associated structures, middle ear, sinuses, lachrymal apparatus (tear ducts) LRT/Lower Respiratory Tract Infections (Usually not colonized) - Bronchial tubes & alveoli (contains alveolar macrophages) Host defenses: - Tortuous airways, nasal hairs, secretions of antimicrobial peptides, saliva (washing & chemicals), mucous membrane (ciliary epithelium, mucus, tight cell-cell junctions, rapid cell turnover, MALT – Mucosal Associated Lymphoid Tissue), alveolar macrophages, & resident microbiota @ the upper respiratory tract o Normal microbiota of the upper respiratory tract (defenses for alternative colonization)  Gram-positive cocci predominates: viridans streptococci, coagulase –ve staphylococci  Gram-positive rods: diphtheroids  Gram-negatives: Haemophilus (rods), Neisseria (cocci)  Colonizing pathogens: S. pneumoniae, S. aureus, S. pyogenes o Mucociliary escalator: Goblet cells embedded between the epithelial cells of the respiratory tract secretes mucus, mucus traps microbes & cilia sweeps mucus out of the respiratory tract Upper Respiratory Tract Infections - Pharyngitis (sore throat): Viral or bacterial infections (H. influenzae, Group C streptococci, non-toxigenic strains of C. diphtheriae), typically self-limiting (recovers spontaneously  adaptive system kicks in) - Streptococcus pyogenes: Normally resides @ the throat can cause Streptococcal pharyngitis (strep throat) o Primarily affects children, person-person spread via respiratory droplets, if spread  tonsillitis o Symptoms: Abrupt onset, fever, enlarged lymph nodes @ neck, headache, posterior pharynx (red, inflamed, patches of adhering pus  specific for strep throat, viruses), hemorrhaged areas - Problem of strep throat: Potential for complications during or after acute pharyngitis o Poststreptococcal sequelae: Develop after untreated acute illness (S. pyogenes no longer present)  Acute glomerulonephritis (Kidney disease)  More related to S. pyogenes that causes skin infections instead of URT infections  Rheumatic fever/Acute rheumatic fever (ARF) (e.g. Chorea – St. Vitus’ dance – Neurological dysfunction with uncontrollable twitching)  Inflammatory process in various tissues (auto-mediated immune diseases)  Can lead to serious complications (chronic rheumatic heart disease), death/disability o Theory I (Similar AA sequences in streptococcal M proteins & myosin) Cross- reaction of anti-strep (anti-M protein) antibodies with heart tissue, antibodies are kept being released even though S. pyogenes are cleared o Theory II Streptococcal products (toxins – SLO, Spe) can directly damage heart tissue, makes it susceptible to immune system attack - Diphtheria: Toxin-mediated, rare because vaccination (DTaP vaccine – diphtheria, tetanus, acellular pertussis) o Diphtheria toxin: 1 recognized virulence factor, model for how bacterial toxin  eukaryotic cells - Corynebacterium diphtheriae: Gram-positive, non-sporeforming, non-motile, pleomorphic (large) rod o Primarily affects children, person-person spread via respiratory droplets, strictly human reservoir, asymptomatically carried in oropharynx or skin o Identification require tellurite containing media (particular artificial media for growth) o Virulence factors  Diphtheria exotoxin (tox gene of temperate bacteriophage)  If absent, causes sore throat  Adherence factors for local colonization in throat/skin o Symptoms: Sore throat, fever, fatigue, malaise, formation of adherent, fibrous pseudomembrane (tight adherence of fibrin resulting in difficulties in breathing/swallowing, local toxin effects due to death of cells, induction of inflammation) on tonsil, pharynx & nasal cavity BIOL444 – Microorganisms & Diseases Fall 2012  Local infection can progress into systematic infections (toxemia)  Systematic: Irregular heartbeat, difficulty swallowing & breathing (airway obstruction), possible kidney failure, paralysis, stupor, coma, death in 10% untreated (Susceptibility depends on the # of host HB-EGF receptors present)  If skin infected: Ulcerating lesions @ areas where diphtheria is endemic o Pathogenesis  Binds host HB-EGF surface protein (Heparin-binding Epidermal Growth Factor)  Highly expressed in young children, lots on heart & nerve cells  Important signal for cell growth & differentiation  Receptor for diphtheria toxin/a-b toxin o Toxin brought into the cells via receptor-mediated endocytosis  A chain: Ribosylates EF-2 (Elongation factor 2) important in protein synthesis (transfers charged tRNA to aminoacyl site of the ribosome)  Termination of protein synthesis  Cell damage & death  ADP-ribosyl of A chain ribosylates & deactivates EF-2 by attaching to the diphthamide residue on EF-2 (all known eukaryotic EF-2)  Mouse, no receptor for B but A can still be toxic if enters  B chain: Binds host receptor, low pH in the endosome (acidification) results in a change in conformation of B chain to form a channel on the endosome  A chain escapes  Purpose of supplying toxin is to kill host cells to obtain Fe  Control of diphtheria a-b toxin expression (bacteriophage gene integrated into diphtheria chromosome) & siderophore translation (diphtheria chromosome) o Diphtheria regulation repressor protein that is always produced by the bacteria  Negative regulation  Excess Fe Repression: Fe (corepressor) binds repressor protein  conformational change  binds +he operator to prevent expression of A-B toxin & siderophore o High [Fe ] results in low level of toxin production  No Fe Activation: No binding of repressor protein to the operator  production of A-B toxin and siderophore to sequester iron + o Low [Fe ] results in high level of toxin production o Prevention & Treatment  Preventive vaccine: Toxoid – formalin-treated toxin (DTaP vaccine)  Inactivated B chain, with A chain that may or may not be completely activated o Uptake by host cell is limited, results in production of protective antibodies o Protection may not be life-long (10 year boosters recommended) o Risk: Non-immunized children  outbreaks  Treatment: toxin antiserum injection ASAP, & administration of erythromycin/penicillin to prevent transmission of bacteria  No aid against illness, toxin is already absorbed (not effected by antibodies) - Whooping cough/Pertussis: Endemic world-wide once, incidence ↓ due to DTaP vaccine; 3 disease stages (catarrhal, paroxysmal & convalescent), usually disease is not diagnosed until the paroxysmal stage (2-4 weeks, whooping symptoms starts to appear, # of bacteria ↓ but enough toxin accumulated) - Bordetella pertussis: Gram-negative coccobacillus, strict aerobe, fastidious, grows on AA not carbohydrates, require blood-charcoal media, & specific cofactor nicotinamide o Strictly human pathogen, mostly affects inadequately-immunized children, adults are significant reservoirs of this exceptionally contagious pathogen, spread via aerosols (secondary spread) o Symptoms: Persistent coughing (black eyes & hemorrhaging), can lead to 2⁰ pneumonia, or multiple systemic infections, the degree of damage on the organ is dependent on the # of receptors BIOL444 – Microorganisms & Diseases Fall 2012  Young children can die of asphyxiation o Pathogenesis: Strong tissue tropism @ upper respiratory tract ciliary epithelium  Colonizes via adhesions (Fha, pili, pertactin, S2 Pertussis toxin), ultimately kills ciliated cells (tracheal cytotoxin) but no invasion of the respiratory tract cells, loss of ciliary escalator  particulate matter to accumulate in respiratory tract  B. pertussis can bind CR3 on phagocytes to initiate phagocytosis “self-initiated phagocytosis”, unknown why because this bacterium cannot survive in phagocytes o Virulence factors:  Adhesins  Filamentous hemagglutinin (Fha): Binds surface molecules on different kinds of cells, and binds CR3 on phagocytes  “self-initiated phagocytosis”  Pertussis toxin (S2 Ptx – modified a-b toxin): S2 binds glycolipids of ciliated respiratory cells & S3 binds to gangliosides of phagocytes (S2-S5 are B subunits)  Pili (Fim2 & Fim3) & Pertactin (B. pertussis specific surface protein)  Toxins (Effects ciliated cells & leukocytes (cells with Ptx receptors), T cell inactivation, loss of phagocytosis & loss of NK)  Pertussis toxin (similar to a-b toxin of C. diphtheriae) o S1 ADP-ribosylates host cell1G -protein that maintains the cell’s ionic concentration via cAMP production, so cell is unable to inhibit adenylate cyclase from converting ATP into cAMP o The Ptx S2-S5 binds receptors on membranes & S1 subunit penetrates the whole cell plasma membrane  Invasive adenylate cyclase (produced in an inactive form, similar to a-b toxin) o Enters host cells, once inside, its activated by calmodulin (eukaryotic host 2+ Ca -binding protein), if activated, catalyses the conversion of ATP to cAMP o No known bacterial activator (only eukaryote activator – calmodulin)  Both Ptx & ACase  Over production of cAMP  Tracheal cytotoxin: o Peptidoglycan fragment released by multiplying B. pertussis during growth phase, binds to ciliated tracheal cells  prevents ciliary action & leads to death if enough toxin accumulated o Virtually identical to cytotoxin produced by Neisseria gonorrhoeae o Secretion of pertussis toxin  Type III: Gram –ves, injection system directly into target cell via pore through both inner & outer membranes of the bacteria & the plasma membrane of the host cell  Similar to a hyperdermic syringe, evolutionary derivative from flagella  Type IV (H. pylori & B. pertussis): Gram –ves, similar to type III, conjugation  Hollow tube through both inner & outer membranes of the bacteria, toxin released into the surrounding environment  Type II: Gram –ves, single peptide released to the periplasm, then specific transport system transports it out through the outer membrane o Treatment & prevention  Prevention vaccines for pertussis (DTP & DTaP)  DTP (old): Whole killed cell, targets colonization, but contains different toxins, so can result in undesirable side effects (convulsions in 0.1% infants)  DTaP (new): Acellular alternatives, decrease
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