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BIOL 444
Christine Dupont

BIOL444 – Microorganisms & Diseases Fall 2012 Set 03 – Diseases of the Skin & Soft Tissue - Skin Associated Lymphoid Tissue (SALT): Collections of T cells, B cells & macrophages (1 line of defense) o Activates specific defence systems to confide invaders & prevent further access into the bloodstream o Skin Protective Agents: Lysozymes, Toxic lipids & By-products o Best growth environment for microbes: Pores, Hair follicles, Sweat glands (physical protection) - Normal Skin Community (Mostly Gram +) - Opportunists o Staphylococci: Coagulase negative (e.g. S. epidermidis) except for S. aureus, all facultative anaerobes o Diphtheroids: Anaerobes @ hair follicles & pores (e.g. Propionibacterium acnes  Acne formation) o Yeast: Small, lipophilic (e.g. Malassezia – Danruff/Skin Shedding & Candida sp. Yeast infections) - Minor Skin Community: o Clostridium perfringens: anaerobes, spore former, normally in soil & water, 20% healthy individuals o Streptococci @ oral cavity or E. coli & Gram – due to fecal contamination Staphylococci - Gram + cocci, tetrads & clusters in pure culture, pairs or single in pus, non-motile, facultative anaerobes, salt- tolerant & catalase + (key for identification), optimal temperature ranges from 10-40⁰C, resist drying - Habitat: Skin, mucous membranes (e.g. External nares & vagina) o S. aureus found commonly @ nasal carriage: 25% infected, transient (Hit & Run Infections) o S. epidermidis found commonly @ skin: catheter infection, opportunists when gets elsewhere - Huge # of S. aureus strains, identification is done by phage typing pattern (groups I to IV). Their resistance to different antibiotics is of particular importance (MRSA: Methicillin Resistant S. aureus) o Bacteria phage attaches specific surface molecules of specific strains of S. aureus, this host-phage specificity is used as a marker to differentiate the genetic differences between strains Diseases caused by Staphylococci (Particular S. aureus) - Different strain  Different toxins due to the specific transducing phage they carry (virulent factor) o Skin & Soft-Tissue Infections  Abscesses/Boils (Stye, Furuncles, Carbuncles) & Wound Infections  Stye: Infected eyelash follicle  Furuncles: Superficial infected hair follicle (No scarring if no squeezing)  Carbuncle: Many infected follicles, starts as furuncles, involves subcutaneous tissue, results in scarring, need to be drained surgically to prevent infection & spreading  Abscesses: Pus-filled (live & dead leukocytes, bacteria, cellular debris, fluid), walled off type (Fibrin-walled capsule “Protective Barrier for immune cells”) o Necrotic, acute inflammation & phagocytes lysed by phagocytising bacteria (lysosomal contents are released, causing tissue damage)  Cellulitis: Infection of the deep soft tissue  Inflammation, spreading type, shiny due to fluid (swelling)  Impetigo: Surface scrape/scratch  spreading type, contagious  Commonly seen in children, rare in adults (If seem, may be immuno-compromised)  Can also be caused by Staphylococci pyogenes o Disease caused by Toxins (virulent factor)  Toxic Shock Syndrome (TSS): Superantigen enters blood stream, not necessarily the bacterium or its cell wall components (Bacteria may colonize elsewhere)  Systematic Inflammation  E.g. Rely Tampons: S. aureus adherences to the synthetic fibres (polyacrylate) used in these tampons, superantigens are absorbed into the bloodstream  sharp ↑ in TSS o Improper tampon usage still contributes to ~50% of TSS today; NEVER leave them in longer than recommended time!  Septic Shock: Due to pathogen cell wall components floating in bloodstream BIOL444 – Microorganisms & Diseases Fall 2012  Scalded Skin Syndrome: Caused by S. aureus infected with transducing phage that produces 2x exfoliating exotoxins - Exfoliative Toxins (destroys desmoglein)  Life-threatening in very young children, rare in adults  Toxin is released into the circulatory system, actual point of infection is hard to locate  Food Poisoning “Acute Gastroenteritis”: Enterotoxin (A-D) Mechanisms of Action of S. aureus - Transmission: Person-to-Person or Person-to-Animal - Key to Pathogenicity: o Entry & Attachment: Strain dependent, usually need some sort of tissue damage to penetrate the skin or the mucosal barrier o Multifactorial virulence: There are no particular gene that causes disease  Genetic knockouts are still able to cause disease (No ↓ in virulence)  Infections usually localized (coagulase barrier), but toxin can spread systematically via blood - Main Pathogenicity Factors: o MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules)  Protein A: Surface bound or released, binds host cell extracellular matrix glycoprotein for adherence (Unique to S. aureus)  Binds Fc “stalk” portion of the antibody (IgG), rather than the antigen binding site  Inhibits complement factor C1 binding to antibodies  No MAC & Opsonization  Inhibits phagocytes C R binding to antibodies  Inhibits Phagocytosis  Fibronectin-Binding Protein: Binds fibronectin (in-between cells)  Colonization (Common)  Collagen-Binding Protein: Binds collagen  Osteomyelitis & arthritis  Clumping Factor: Binds Fibrinogen/Fibrin (Produced to form clot in response to tissue damage), creates Fibrin clot barrier  blood clotting (Common)  Coagulase: Binds plasma prothrombin (Fibrinogen  Thrombin-like Complex  Fibrin clot) creates Fibrin clot barrier (Human-origin member genus)  Fibrin clot barrier  Walling off wound  Need for abscess development  When knocked-off, disease progresses as a spreading type, changes disease profile  Coagulase Test doesn’t distinguish between Coagulase vs. Clumping Factor (S. aureus has both) [S. aureus: Catalase +, Coagulase +, Gram + cocci]  Capsule “Slippery Surface w/ Multi-Purpose”: Avoidance of phagocytosis, some also promote adherence to tissues (Different polysaccharides for different sstains) o Lipases: Lyse lipids, allows invasion into dermal layer by hydrolysis oils on skin “1 step of attachment” o Hemolysins “Lyse RBCs”: Produces hemolysis on SBA, exotoxin (secreted), 4 types (Varies with strain)  α-toxin: Principle hemolysin of human strains, doesn’t lyse human RBC, only platelets & cells  Pore-forming cytotoxin, many cells have receptors for α-toxin (e.g. phagocytes) o Pore: Monomers oligomerize to produce hexameric ring w/ central pore o Insertion: Lipid-binding domain inserted into lipid bilayer  Disrupts protein motive force & loses ionic balance  Contributes to tissue necrosis & invasion, the bacterial version of the MAC complex  β-toxin: Hemolysis animal strains  γ-toxin: Only active against certain species  δ-toxin: Widespread cytotoxin (lysis of cells) o Superantigens: Phage encoded toxins that directly interacts w/ TCRs & MHC II of APCs  Enhanced T cell Response  Overreacting host defenses  Shock (Toxic Shock Syndrome/TSS)  Normally: 2 check-points involved, antigen on MHC II binds TCR & MHC II binds CD4 Co- Receptor  Specific CD4 T cells are activated due to the specificity of the antigen  Limited cytokine production BIOL444 – Microorganisms & Diseases Fall 2012  Diseased: Superantigen directly cross-link MHC II molecule w/ TCR, no antigen is needed and no CD4 Co-Receptor needed, any CD4 T cell can be linked & activated  Expansion of MANY + DIFFERENT CD4 T cells (80%+ of T cells can be activated) Excess cytokine production  Systematic Inflammatory Response  Toxic shock  Enterotoxins (A-G): “Gut-Associated Toxins”, not as potent as TSS causing toxins, responsible for food poisoning (acute gastroenteritis) (50% of strains)  A-D: Major cause of acute food poisoning, inhibits H O reabsorption (diarrhea) & 2 interact with emetic receptor sites @ GI tract (induce vomiting), & cramps  Self-limiting (24-48h), effect are due to presence of toxin (pathogen may already be gone) (enterotoxin production does not stop @ the fridge, can be destroyed by proper cooking & S. aureus doesn’t colonize @ GI tract)  Purpose of Superantigen production?  Induce mid-directed immune response, pathogens are not dealt w/ directly, hence pathogen escapes the adaptive immune system  However, S. aureus doesn’t colonize inside the GI tract (only skin, vagina & nasal); superantigens may provide advantages in a competitive way @ normal environment?  Advantage for the phage?  Easier for the phage to replicate in their specific host cell “bacterial farming” o Exfoliative Toxins: Toxins delivered by phage, exotoxins, systemic effects (Group II strains), disrupts intercellular junctions (desmosomes) between epidermal cell layers  epithelial desquamation “Shedding of Skin” “Scalded Skin Syndrome”  ET-A targets desmoglein-1 (DSG-1): Protein that maintains keratinocyte cell-cell adhesion  ETs are antigenic, hence toxin-neutralizing antibodies will be eventually produced by the host so the disease doesn’t re-occur again  Occurs in very young children or immuno-compromised adults o Panton-Valentine (PV) Leukocidin: Toxins delivered by phage, pore-forming cytotoxins enters the host cell through pores, kills phagocytes & epithelial cells by damaging the mitochondria (2-5% strains)  Responsible for 90% of necrotizing skin & lung infections  Much more dangerous than α-toxin of hemolysins  Most people mount protective immune responses, usually occurs in very young children or immuno-compromised adults (PV Leukocidin-producing MRSA strains are very dangerous) o Extracellular Bioactive Substances (Abscess vs. spreading): Unclear roles  Hyaluronidase: Hydrolyzes matrix of connective tissue, spreading type (90% of strains)  Staphylokinase (fibrinolysin “clot buster”): activates plasminogen “dissolve clots”  fibrin clot dissolution, spreading type, can be a factor in furuncle (coagulase) vs. impetigo (staphylokinase)  Nucleases, lipases, proteases o Other:  Transferrin-binding proteins: Steal iron from host transferrin  β-lactamase: Penicillinase, transmitted by phage, resistance to safer antibiotics (all strains) - Summary of Pathogenesis: o S. aureus enters wound  lipases hydrolyzes protective oils  attaches to dermal cells via MSRAMMs  Inflammation  Neutrophils & Macrophages called in  Antiphagocytic activity by Protein A, PV Leukocidic & α-toxin release  Some escapes & phagocytes are destroyed  More inflammation & necrosis  Coagulase sets up fibrin barrier (abscess) or escapes to other tissue (systematic) - Treatment, Prevention & Control o Antibiotic Therapy: Semi-synthetic penicillin (Penicillin w/ side groups, more resistant to β lactamase)  MRSA (Methicillin-resistant S. aureus)  VISA (Vancomycin-resistant S. aureus)  Methicillin: Group of modified penicillin in β-lactam class of antibiotics BIOL444 – Microorganisms & Diseases Fall 2012 o Modified hence its β-lactam ring cannot be broken down by β-lactamase o Function by binding & inhibiting the Transpeptidase/Penicillin-Binding Proteins (PBPs) that cross-link peptidoglycans of the cell wall (Gram +)  Gram – has much thinner peptidoglycan layer & an outer membrane  By inhibiting PBPs, microbes cannot make enough peptidoglycans to build the layer during cell division, cease to grow or lyse  MRSA (3 Methods) o Produce β-lactamase (Inactivate drug): degrades β-lactam Ring (all strains) o Alteration of drug target sites: PBPs  Change genes encoding PBP via natural genetic mutation, modified PBPs no longer bind methicillin-type drugs  S. aureus have 5 PBPs that are all sensitive to methicillin, MRSA acquired 6 PBP (mecA) that is resistant to methicillin binding o Reduce entry into periplasmic space (Drug inaccessibility) (Gram -)  Specific for Gram – outer walls, bacteria develops structural changes @ outer membrane to block transport of the antibiotics  Vancomycin: Group of glycopeptide antibiotic (not β-lactam) o Also inhibits peptidoglycan synthesis, but bind directly to the peptidoglycan building blocks (not PBPs), blocks the ability of PBrd to cross-link o Fairly toxic because it also binds some host peptides (3 line of antibiotic, drug of last resort) o Vaccines: Limited success o Contact Prevention: Difficult, Staphylococci are ubiquitous (unknown if potentially deadly or normal)  Best: Hand-washing, coverage of exposed skin surfaces, disinfectants o Development of Resistant Microbes (Antibiotics selects for highly resistant microbes)  Normal drug treatment + Immune clearance: Infection is controlled so the immune response working in synergy will prevent disease from recurring  Random mutation of microbes results in some more potent to be drug resistant, but overall no detectable microbes (will be taken care of by the immune system)  Normal drug treatment + Immuno-compromised individual: Infection is controlled by the drugs, but the more resistant mutant strains of microbes will not be eliminated due to the absence of normal immune response, further genetic changes & further drug treatment results in the proliferation of highly resistant strains of microbes  Premature drug treatment termination + Immune clearance: Infection is not totally controlled by the drug, rebounding populations of microbes cannot be taken care of by the immune system, with further genetic changes, highly resistant strains of microbes develop, now the antibiotics are not working o Microbes “Masters of Evolution”: Horizontal Gene Transfer by Phage that aids in Evolution  Transfers between different species  Resistance develops way too fast for just random mutations  E.g. E. coli O157:H7 (Shigella virulent factors transferred to E. coli) Streptococcus - Gram + cocci, in pairs or chains, aerotolerant anaerobe2 (O tolerant, but lives normally in environments with no O2), nutritionally fastidious (loves rich media), fermentative (carbohydrates  lactic acid), catalase – - Categorized by: o Clinical presentation: Pyogenic (pus-formation), oral (@ mouth) & enteric (GI tract) o Hemolysis pattern on blood agar: α, β, or γ o Lancefield grouping: Based on cell wall carbohydrate (Antibody – Surface Antigen testing) (A - T)  Streptococci pyogenes: β-hemolytic streptococcus + Group A BIOL444 – Microorganisms & Diseases Fall 2012 o Biochemical & Physiological Characterization: Streptococcus, Lactococcus, Enterococcus - Viridans streptococcus sp. w/ α, β or γ hemolysis o Streptococcus sp. of normal oral flora or S. pneumoniae: α-hemolysis “greenish zone”
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