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28 Cards in this Set
- Front
- Back
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Staphylococci general |
Gram positive non-motile, non-spore 1micrometer in diameter facultative anaerobes CATALASE-POSITVE(not Strep) |
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G+ membrane |
1.Capsule 2. Thick peptidoglycan layer -lipotechoic acid LTA(2) either embedded in peptidoglycan layer or anchored to plasma membrane 3. Cytoplasmic membrane |
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Major human pathogens |
1. Staphylococcus aureus -coagulase positive -staphyloxanthin(carotenoid pigment) results in golden pigmentation. 2. Staphylococcus epidermidis -coagulase negative -white pigmentation -biofilm on plastic implants and indwelling devices 3. Staphylococcus saprophyticus -Coagulase negative -Urinary tract infection S. epidermidis and saprophyticus lack most of the virulence factors of S. aureus |
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coagulase test |
Staphylocoagulase is responsible for blood clot formation. - NOT an enzyme - secreted protein that forms staphylothrombin complex by binding prothrombin(trypsin-like ser protease). - protease activity of prothrombin activated : conversion of fibrinogen to fibrin(blood clot formation) |
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Staphylococci are part of normal microflora |
S. aureus in nose of 20-30% population S. epidermidis is common on skin Opportunistic pathogens: --> disease occurs when staphylococci or exotoxins breach epithelial layer and access deeper tissues |
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Nasal colonization by S. aureus |
Human genetic factors seem to be responsible for persistent colonization -single-nucleotide polymorphism predisposing to S. aureus in glucocortoid receptor, IL-4 and C-reactive proteins. -in nose, in a state favoring adhesion rather than virulence -Still is a risk for infection--> colonized humans more prone to develop severe infections |
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Clinical manifestations |
S. aureus responsible for disease from mild to fatal Severity depends on strain and where colonization takes place 1.Skin infections 2. Osteomyelithis 3. Septic arthritis 4. Abscesses 5. nectrotizing pneumonia 6. infective endocarditis (heart valve) 7. Sepsis --> 20 30% death rate 8. Food poisoning and SAgs (toxic shock syndrome) |
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Antibiotic resistance |
S. aureus is the leading cause of hospital-associated infections -1990s appearing of CA-MRSA -2002 first case of VRSA (vancomycin associated_ |
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CA-MRSA |
Most CA-MRSA are PVL(penton-valentine leukocidin) positive in contrast to to only 2% of S. aureus are PVL positive.(encoded by a prophage) -pore-forming toxin targetting neutrophils and macrophages (not lymphocytes) -therefore in order to become CA-MRSA, S. aureus must first acquire PVL from phage. |
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Virulence factors of S. aureus |
Different strains produce different virulence factors and cause different diseases -many virulence genes are carried by phages, DNA mobile elements or plasmids. |
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Adherence to host proteins |
Adhesins are known as MSCRAMMs -bind proteins from ECM -Important role in colonizing tissues -MSCRAMMs covalently linked to peptidoglycan cell wall. -C-terminal sorting signal (LPXTG motif) -Different MSCRAMMs bind to different target |
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Sortase mediated anchoring of MSCRAMMs |
1, Sortase recognizes LPXTG motif, cleaves btw threonine and glycine 2. Forms amide bond btw threonine and lipid II pentaglycine |
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Diversity of Sortase |
Virulence factors essential to pathogenesis 1. Srt A - housekeeping -Adhesion -Immune evasion -Internalization -Phage recognition 2. Srt B - iron acquisition 3. Srt C - pili formation -NOT found in S. aureus 4. Srt D - spore formation- NOT found in S. aureus |
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SrtA 3D structure |
- beta barrel with 8 beta strands -Cysteine 184 and histidine 120 essential for sortase activity and are conserved among sortase proteins. - Sortase is a good target for new antimicrobials. |
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Sortase inhibitors(AAEK) |
high-throughput screening identified AAEK (aryl-beta-amino(ethyl) ketone) -active site cysteine of sortase forms a covalent bond w/ AAEK and sortase is irreversibly inactivated.
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Iron acquisition by S. aureus |
1. siderophores(3) -Staphyloferrin A -Staphyloferrin B -Aureochelin 2. Surface transferrin receptor + iron transport system 3. Hemoglobin-binding protein and heme-iron transport system (iron-regulated surface determinant, isd locus)(has NPQTN sequence motif) |
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Isd locus |
low iron condition: Fur dissociates from fur box upstream of Isd --> expression of Isd 1. SrtA attaches IsdA/B to cell wall 2. SrtB is specific for NPQTN sequence motifs and covalently attaches isdC to cell wall. |
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Isd locus mechanism of action |
- IsdB binds hemoglobin (Hb) and transfers iron containing heme to IsdA, IsdC and to permease transport complex IsdDEF. -in cytoplasm: monoxygenase (IsdG) oxidative degradation of heme to release iron. - 75% of iron is bound to hemoglobin, only 7% to transferrin |
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Quorum sensing in S. aureus |
-In G+, quorum sensing : autoinducer peptides (AIPs) exported by specific transporters (AgrB) -Extracellular peptides are recognized by histidine kinase sensor (AgrC) -The sensor autophosphorylates and transfers phosphoryl group to AgrA cognate response regulator (a TF) -AgrA activates/represses specific genes |
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AIP subgroups |
-Short peptides(7-9residues) containing thiolactone ring structure -classified in 4 subgroups(different strains/species have different)] AIP) -they cross-inhibit between subgroups(AIP-1 activate agr of AIP-1 producing cell, inhibit virulence strains of other) |
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AgrC regulated by AIPs |
AgrC has N-terminal sensing domain and histidine kinase in cytoplasm 1.AIP-1 binding to AgrC-1(agonist): CCW rotation of linker + autophosphorylation + agr activation 2. AIP-2 binding to AgrC-1(antagonist): CW rotation of linker + agr repression |
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agr in quorum sensing |
accesory gene regulator: -AgrB processes and exports AIP(product of agrD gene). -AgrC senses AIP and phosphorylates AgrA -AgrA promotes transcription of P2(Agrs) and P3(RNAIII) |
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RNAIII |
small RNA that consists of 514 nt and is highly structured -5' end contain ORF coding for delta-hemolysin(pore forming toxin of s. aureus) -3' end is antisense RNA that inhibits cell wall anchor protein -3' end can also upregulate other virulence genes |
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Immune evasion: complement evasion: protein A |
Protein A contain 5 Ig-binding domains in tandem -each domain can bind FCgamma (constant region of IgG) preventing opsonization and phagocytosis -lacking protein A --> less virulent |
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Complement evasion:staphylokinase |
SAK activates plasminogen into plasmin w/out cleavage) -Plasmin is a serine protease that cleaves IgG and C3b --> impaired phagocytosis |
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Complement evasion: CHIPS |
Chemotacis inhibitory protein -binds and inhibit C5aR and FPR(formyl peptide receptor) resulting in neutrophil chemotaxis inhibition. |
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Capsular polysaccharides |
-11 different serotypes -types 5 and 8 account for 25 and 50% of human infections -most MRSA are type 5. -play a role in preventing interaction btw C3b and complement receptor on neutrophils --> prevent phagocytosis |
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Vaccines S. aureus |
unsuccesful -StaphVax: conjugate polysaccharides type 5 and 8 to P.aeruginosa exotoxin A. 57% efficacy. |
