Pathogenic Micr PATB 2220
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Date Created: 10/27/15
MOLB 2220 Pathogenic Microbiology Lecture 3 Mechanisms of Bacterial Virulence An Overview Introduction History 1800 s to date Physiology of bacteria under study 1890 Exotoxin of Clostridium tetani discovered 1903 Toxic substance from ShigeIa identified 1931 polysaccharide capsule associated with virulence of Streptococcus 1941 One geneone enzyme concept 1944 Transforming principal The transforming principal is DNA Extract DNA and add to rough bacteria Dead mouse Bacteria Mouse has iive contain dies smootbbacieria DNA Heatkilled smooth bacteria g Transformation iive rough bacteria 3 Obtain smooth bacteria from Lewin Genes Wiley amp Sons publishers 1987 History cont 1953 WatsonCrick HersheyChase experiment 1954 Toxic factor of anthrax identified 1956 Key virulence protein of Y pestis plague discovered 1958 DNA replication concept of operon Birth of Molecular Pathogenesis Key Nobel Prizes 1958 Beadle and Tatum for their discovery that genes act by regulating definite chemical events and Lederberg quotfor his discoveries concerning genetic recombination and the organization of the genetic material of bacteriaquot 1962 Watson Crick and Wilkins quotfor their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living materialquot 1969 Hershey Chase Luria and Delbruck for their discoveries concerning the replication mechanism and the genetic structure of viruses Koch s Molecular Postulates A specific gene should be consistently associated with the virulence phenotype When the gene is inactivated the bacterium should become avirulent If the wild type gene is reintroduced the bacterium should regain virulence If genetic manipulation is not possible then induction of antibodies specific for the gene product should neutralize pathogenicity From Falkow 1988 Rev Infect Dis Vol 10 suppl 28274276 General Properties of Pathogenicity Complex multiple virulence factors Different sets of virulence factors cause different diseases Although change of a single factor may change disease Example EPEC versus EHEC infection Acquisition of large blocks of genetic material Not slow evolution mutation of existing genes Mobile DNA mainly plasmids Example Antibiotic resistance markers Pathogenicity Islands Examples Ecoli haemolysin E coli Ppili Characteristics of Virulence Factors Virulence factor virulence determinant Gene andor gene product Stringently or loosely regulated in the bacterium Expression of multiple virulence factors confer the disease producing properties on the pathogen Required for virulence or merely enhance it Proteins or nonproteins Defined or undefined biologic function with defined or undefined mechanisms of action Single or multiple functions effects Common Themes in Bacterial NFDP PWNT Pathogenesis Toxins Adherence Invasion Intracellular lifestyle Host Immune Modulation Iron Acquisition Secretion Mechanisms Gene Regulation Bacterial Toxins Direct enzymatic mechanism which effects target cells Facilitate spread through tissues Damage cell membranes lmmunomodulatory Inhibit protein synthesis Inhibit release of neurotransmitters Single cause for disease orjust a contributor Anthrax vs Shigellosis Categories Subunit Proteolytic Poreforming Cytoskeletol modulators CM toxins Pyrogenic P PWNT Subunit AB Toxins A subunit enzymatic toxic activity Protein synthesis inhibitors Examples E coli LT cholera toxin Shiga toxin Adenylate cyclases Example anthrax edema factor B subunit Mediates binding to host cell receptor Host gangliosides glycolipids or glycoproteins Facilitates translocation ofA subunit Pro teolytic Toxins Zinc metalloendoproteases Neuropathologic effects Inhibit release of neurotransmitters Deliverydependent disease presentations Oral example Botulinum toxin causes flaccid paralysis Cleaves synaptobrevin to inhibit release of acetylcholine in peripheral nerves Wound example Tetanus toxin spastic paralysis Cleaves synaptobrevin to inhibit release of acetylcholine in the CNS Proteolytic Toxins cont Immunoglobulin A IgA proteases Made by pathogens that colonize mucosal surfaces Examples Haemophilus Neisseria Serratia Helicobacter Unlike some other toxins does not require elaborate secretion system autosecreted by the bacterium Specifically cleaves secretory lgA1 Poreforming Toxins RTX family Produced by many Gram negative pathogens Example E coli haemolysin Induce cytolytic effects by insertion into the target cell membrane Sulfhydrylactivated family Produced by Gram positive pathogens Example L monocytogenes Listeriolysin O Mediates escape from macrophage vacuole Activity triggered by low pH CM Toxins Alter host cell actin filament polymerization state Antiphagocytic andor Necrotic effects Yersinia Outer Proteins YOPs E coli cytotoxic necrotizing factorl CNF1 Enhance cellcell interactions example EPEC Pedestal Pyrogenic Exotoxins Superantigens Potent activators of Tcells Suppress Bcell responses Enhance susceptibility to LPS Stimulate cytokine production Examples Staphylococcus enterotoxin B SEB S aureus toxic shock syndrome toxin Normal antigen presentation Action at superamigens b Antigen Superanligen H ow superantlgen toxins work A x Small sunset 0 TCEHS Excess uroducxiun of IL2 Cymklnes 1especxauy lLZ Pralilera on Stimulates cell praduc cn a TNFu and l er cywkmes V by other cells T can a cell interacuon V from Salyers AA Shack and D D Whit eds 1594 39 Bacterial Pathogenesis Pmlimauan A Molecular ASM Press a B cells 39 I V Fmducuon of anubcdy Adherence Requisite to colonization andor invasion Mediated by adhesins Bind host cell receptors andor extracellular matrices Surface macromolecular structures polymers Fimbrial P Pap pili Type IV pili somatic pili Fibrillar Yersinia YadA and pH6 Ag E coli curli Other afimbrial adhesins B pertusis and Haemophilus FHA High molecular weight secreted monomer Classic vs Curli A few words about Flagella Large filamentous polymeric structures Required for motility Tactic response nutritional andor physical Single or multiple strands Bundled or dispersed Virulence factor in SOME pathogens Example V cholerae Flagellar motor assembly may be more relevant to virulence Evolution of the TypeIll protein secretion system TTSS Flagellar Arangement and Motor Apparatus monotrichous lopho peri Peptidoglycan from Brock Biology of Microorganisms 3rd Ed Prentice Hall Inc 1979 Invasion Many bacterial pathogens can escape from the vacuole of a phagocyte andor gain entry into nonphagocytic host cells lnvasins Two types Disrupt cytoskeletol architecture Host receptormediated Similar to CM toxins Examples Yersinia lnv Shigela lpa Direct membrane digestion Phospholipases example Rickettsia Intracellular Lifestyle SurvivalGrowth of pathogen within phagocytes andor nonphagocytic cells Modification of the phagocytic vacuole Inhibition of lysosomal fusion eg Brucela Induction of coiling phagocytosis Examples Legionela Borreia Transcytosis example Salmonella Movement through target cell and release Escape from the vacuole Lysis of the vacuolar membrane Examples Yersinia YopBD Shigela lpaB Listeria listeriolysin O Movement of bacteria in cytoplasm via host actin filaments Examples Shigela lscA Listeria ActA Coiling Phagocytosis MACRO CONVENTIUNAL COILING PINOCYTOSIS PHAGOCYTDSIS PHAGOCYTOSIS from Ritteg et al 1998 Infect Immun 66627 Intracellular Virulence Factors O2 radical neutralizers example Brucela Resistance to bactericidal cationic peptides example Legionella Proteases which degrade lysosomal proteins example Salmonella Inhibition of vacuole acidification Example Mycobacterium Alternative Lifestyle Resistance to phagocytosis Capsule Polysaccharide example S pneumoniae capsule Protein example Y pestis F1 antigen Fimbriae pili example Group A Streptococcus Other surface molecules Example Streptococcal M protein Induction of apoptosis Programmed cell death Contactdependent secreted virulence factors Examples Yersinia YopJ Shigela lpaB note multifunctional Immune Modulation Degradation of immune components lgA proteases examples H influenza Clostridium Complement proteases example S pneumoniae Cytokine proteases example Y pestis Downregulation andor upregulation of cytokines Induces wrong immune response Examples Brucela Burkholderia Numerous virulence factors mostly uncharacterized Immune Avoidance Masking of the bacterial surface Example Staph Protein A binds immunoglobulin Antigenic variation pili flagella LPS capsule secreted enzymes outer membrane proteins Gonococcal pilus Rearrangements of over 50 copies of the pilin subunit gene Salmonella LPS 0 sidechain Over 60 different serotypes Iron Acquisition Essential to survival in and out of the host Free iron severely limited within the host Iron acquisition systems Membranebound receptors Interact with host ironbinding proteins such as human lactoferrin and transferrin Secreted siderophores Steal iron from host Moves into the pathogen by a specialized transport system Bacterial Protein Secretion What s In and What s Out Virulence factors must traverse two membranes in Gram negative pathogens IM General Secretory Pathway GSP OM Protein secretion transport mechanisms Simple More Complex Typel Autotransporting Type II Single Accessory Pathway Type III ChaparoneUsher Type IV Protein Secretion Systems The Simplest b Autt transpomar A Single accessory pa way pathway mmm Current Opinion in Cell Biology Protein Secretion Systems Types I and II M SM Pen39plasm a a In In roe v 1 i saw C Protein Secretion Systems Types III and IV 552111311331 To eukaryonc cell T Flageuar biogenesis Type III secretion eeeeee p man m 001 Bwolwgy Virulence Gene Regulation What s Hot and What s Not Requirements for survival outside the host versus inside the host could be quite different Most virulence genes are tightly regulated by a number of environmental cues but some are more loosely regulated than others Y pestis F1 capsule gt Temperature Y pestis plasminogen activator Pla Regulation is usually tiered nonsequencespecific and sequencespecific regulators Conditions affecting expression Temperature pH osmolarity O2 tension metabolites ions cell density others Summary Bacterial pathogenicity is complex many virulence factors Expression of virulence factors are regulated in the host environment Virulence is characterized by common mechanisms themes Bacterial pathogens continue to evolve
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