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Important Protozoan Pathogens Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. • Infectious ciliates – Balantidium coli–a zoonotic disease acquired by humans via the fecal-oral route from the normal host, the pig, where it is asymptomatic. Contaminated water is the most common mechanism of transmission. . Apicomplexa Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cytostome Food vacuoles Nucleus Cell membrane Cytostome (mouth) Food vacuole Nucleus Endoplasmic reticulum Mitochondrion © (a) ASM Michael Riggs et al, Infection and Immunity, Vol. 62, #5, May 1994, p. 1931 (b) 2 2 Important Protozoan Pathogens • Infectious apicomplexansPlasmodium species: Cause of malaria; • Toxoplasma gondii: Cause of Toxoplasmosis • Cryptosporidium sp.: Cause of Cryptosporidiosis Parasitic Helminths • Multicellular animals; organs for reproduction, digestion, movement, protection • Parasitize host tissues • Have mouthparts for attachment to or digestion of host tissues • Most have well-developed sex organs that produce eggs and sperm • Fertilized eggs go through larval period in or out of host body 4 Helminth Classification and Identification • Classify according to shape, size, organ development, presence of hooks, suckers, or other special structures, mode of reproduction, hosts, and appearance of eggs and larvae • Identify by microscopic detection of worm, larvae, or eggs Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oral sucker Pharynx Esophagus Intestine Ventral sucker Cuticle Vas deferens Uterus Cuticle Ovary Testes Scolex (a) Seminal receptacle Proglottid Suckers Immature eggs Fertile eggs (b) Excretory bladder 5 Major Groups of Parasitic Helminths 1. Flatworms – flat, no definite body cavity; digestive tract a blind pouch; simple excretory and nervous systems • • Cestodes (tapeworms) Trematodes or flukes, are flattened, nonsegmented worms with sucking mouthparts 2. Roundworms (nematodes) – round, a complete digestive tract, a protective surface cuticle, spines and hooks on mouth; excretory and nervous systems poorly developed 6 The Position of Viruses in the Biological Spectrum • There is no universal agreement on how and when viruses originated • Viruses are considered the most abundant microbes on earth • Viruses played a role in the evolution of Bacteria, Archaea, and Eukarya • Viruses are obligate intracellular parasites 7 General Structure of Viruses • Capsids – All viruses have capsids (protein coats that enclose and protect their nucleic acid) – The capsid together with the nucleic acid is the nucleocapsid – Some viruses have an external covering called an envelope; those lacking an envelope are naked – Each capsid is made of identical protein subunits called capsomers Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Capsid Nucleic acid (a) Naked Nucleocapsid Virus Envelope Spike Capsid Nucleic acid 8 (b) Enveloped Virus Types of Viruses Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. A. Complex Viruses B. Enveloped Viruses Helical Icosahedral (1) (3) (5) (2) (4) (6) C. Nonenveloped Naked Viruses Helical Icosahedral (8) (7) (9) A. Complex viruses: (1) poxvirus, a large DNA virus (2) flexible-tailed bacteriophage B. Enveloped viruses: With a helical nucleocapsid: (3) mumps virus (4) rhabdovirus With an icosahedral nucleocapsid: (5) herpesvirus (6) HIV (AIDS) C. Naked viruses: Helical capsid: (7) plum poxvirus Icosahedral capsid: (8) poliovirus (9) papillomavirus 9 Nucleic Acids • DNA viruses – Usually double stranded (ds) but may be single stranded (ss) – Circular or linear • RNA viruses – Usually single stranded, may be double stranded, may be segmented into separate RNA pieces – ssRNA genomes ready for immediate translation are positive-sense RNA – ssRNA genomes that must be converted into proper form are negative-sense RNA 10 Modes of Viral Multiplication General phases in animal virus multiplication cycle: 1. Adsorption – binding of virus to specific molecules on the host cell 2. Penetration – genome enters the host cell 3. Uncoating – the viral nucleic acid is released from the capsid 4. Synthesis – viral components are produced 5. Assembly – new viral particles are constructed 6. Release – assembled viruses are released by budding (exocytosis) or cell lysis 11 Adsorption and Host Range • Virus coincidentally collides with a susceptible host cell and adsorbs specifically to receptor sites on the membrane • Spectrum of cells a virus can infect – host range – Hepatitis B – human liver cells – Poliovirus – primate intestinal and nerve cells – Rabies – various cells of many mammals Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Envelope spike Host cell membrane Capsid spike Receptor Host cell membrane Receptor 12 (a) (b) Replication and Protein Production • Varies depending on whether the virus is a DNA or RNA virus • DNA viruses generally are replicated and assembled in the nucleus • RNA viruses generally are replicated and assembled in the cytoplasm – Positive-sense RNA contain the message for translation – Negative-sense RNA must be converted into positive-sense message 13 Release • Assembled viruses leave the host cell in one of two ways: – Budding – exocytosis; nucleocapsid binds to membrane which pinches off and sheds the viruses gradually; cell is not immediately destroyed – Lysis – nonenveloped and complex viruses released when cell dies and ruptures Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (b) © Chris Bjornberg/Photo Researchers, Inc. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Host cell membrane Viral nucleocapsid Viral glycoprotein spikes Cytoplasm Capsid RNA Budding virion (a) Viral matrix protein Free infectious virion with envelope 14 Damage to Host Cell Cytopathic effects (CPE) – virus-induced damage to cells 1. Changes in size and shape 2. Cytoplasmic inclusion bodies 3. Inclusion bodies 4. Cells fuse to form multinucleated cells 5. Cell lysis 6. Alter DNA 7. Transform cells into cancerous cells Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Multiple nuclei Normal cell Giant cell CDC (a) CDC Inclusion bodies 15 (b) © Massimo Battaglia, INeMM CNR, Rome Italy Viral Damage • Some animal viruses enter the host cell and permanently alter its genetic material resulting in cancer – transformation of the cell • Transformed cells have an increased rate of growth, alterations in chromosomes, and the capacity to divide for indefinite time periods resulting in tumors • Mammalian viruses capable of initiating tumors are called oncoviruses – Papillomavirus – cervical cancer – Epstein-Barr virus – Burkitt’s lymphoma 16 Lysogeny: The Silent Virus Infection • Not all phages complete the lytic cycle • Some DNA phages, called temperate phages, undergo adsorption and penetration but don’t replicate • The viral genome inserts into bacterial genome and becomes an inactive prophage – the cell is not lysed • Prophage is retained and copied during normal cell division resulting in the transfer of temperate phage genome to all host cell progeny – lysogeny • Induction can occur resulting in activation of lysogenic prophage followed by viral replication and cell lysis 17 Prions Diseases Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Common in animals: • Scrapie in sheep and goats • Bovine spongiform encephalopathies (BSE), a.k.a. mad cow disease • Wasting disease in elk • Humans – Creutzfeldt-Jakob Syndrome (CJS) Brain cell Prion fibrils © James King-Holmes/Institute of Animal Health/Photo Researchers, Inc. (a) 18 Dr. Art Davis/CDC (b) Other Noncellular Infectious Agents • Satellite viruses – dependent on other viruses for replication – Adeno-associated virus – replicates only in cells infected with adenovirus – Delta agent – naked strand of RNA expressed only in the presence of hepatitis B virus • Viroids – short pieces of RNA, no protein coat; only been identified in plants 19 The Metabolism of Microbes Two types of chemical reactions: Catabolism – degradative; breaks the bonds of larger molecules forming smaller molecules; releases energy Anabolism – biosynthesis; process that forms larger macromolecules from smaller molecules; requires energy input Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Synthesis of Cell Structures Macromolecules Carbohydrates Proteins Lipids Sources of energy Carbohydrates Lipids Proteins Catabolism Releases energy End products with reduced energy CO2, H2O ATP NADH Anabolism Requires energy Simple building blocks Sugars Amino acids Increasing complexity Metabolism – all chemical and physical workings of a cell 20 Enzymes • Enzymes are biological catalysts that increase the rate of a chemical reaction by lowering the energy of activation (the resistance to a reaction) • The enzyme is not permanently altered in the reaction • Enzyme promotes a reaction by serving as a physical site for specific substrate molecules to position Energy State of Reaction Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Reactant Energy of activation in the absence of enzyme Energy of activation in the presence of enzyme Initial state Products Final state Progress of Reaction 21 Enzyme Structure • Simple enzymes – consist of protein alone • Conjugated enzymes or holoenzymes – contain protein and nonprotein molecules – Apoenzyme – protein portion – Cofactors – nonprotein portion • Metallic cofactors: iron, copper, magnesium • Coenzymes, organic molecules: vitamins Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Coenzyme Coenzyme Metallic cofactor Apoenzymes Metallic cofactor 22 Cofactors: Supporting the Work of Enzymes Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chemical group (Ch) Substrate 2 (S2 ) • Micronutrients are needed as cofactors • Cofactors act as carriers to assist the enzyme in its activity 1. An enzyme with a coenzyme positioned to react with two substrates. Substrate 1 (S1) Coenzyme (C) Enzyme complex (E) Ch S2 2. Coenzyme picks up a chemical group from substrate 1. C E S2 3. Coenzyme readies the chemical group for transfer to substrate 2. S1 Ch S1 C E Ch S1 4. Final action is for group to be bound to substrate 2; altered substrates are released from enzyme. C E S1 23 Regulation of enzyme action Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Noncompetitive Inhibition Competitive Inhibition Normal substrate Substrate Competitive inhibitor with similar shape Active site Both molecules compete for the active site. Regulatory site Enzyme Regulatory molecule (product) Enzyme Reaction proceeds Enzyme Reaction is blocked because competitive inhibitor is incapable of becoming a product. Reaction proceeds Product Reaction is blocked because binding of regulatory molecule in regulatory site changes conformation of active site so that substrate cannot enter . 24 Enzyme repression Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 DNA 2 3 RNA 4 Folds to form functional enzyme structure Protein Enzyme + Substrate 5 Products 6 7 DNA RNA Excess product binds to DNA and shuts down further enzyme production. Protein No enzyme 25 Biological Oxidation and Reduction • Redox reactions – always occur in pairs • There is an electron donor and electron acceptor which constitute a redox pair • Process salvages electrons and their energy • Released energy can be captured to phosphorylate ADP or another compound Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oxidation C6H12O6 + 6O2 → 6CO2 + H2O + Energy h Glucose Reduction 26 Pathways of Bioenergetics • • • Bioenergetics – study of the mechanisms of cellular energy release Includes catabolic and anabolic reactions Primary catabolism of fuels (glucose) proceeds through a series of three coupled pathways: 1. Glycolysis 2. Kreb’s cycle 3. Respiratory chain, electron transport 27 Metabolic Strategies • Nutrient processing is varied, yet in many cases is based on three catabolic pathways that convert glucose to CO2 and gives off energy • Aerobic respiration – glycolysis, the Kreb’s cycle, respiratory chain • Anaerobic respiration – glycolysis, the Kreb’s cycle, respiratory chain; molecular oxygen is not the final electron acceptor • Fermentation – glycolysis, organic compounds are the final electron acceptors 28 Biosynthesis and the Crossing Pathways of Metabolism • Many pathways of metabolism are bi-directional or amphibolic Anabolism Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chromosomes Enzymes Membranes Cell wall Storage Membranes Storage Nucleic acids Proteins Starch Cellulose Lipids Fats Nucleotides Amino acids Carbohydrates Fatty acids Cell structure Macromolecule Building block Beta oxidation Deamination Glycolysis GLUCOSE Metabolic pathways Catabolism Pyruvic acid Acetyl coenzyme A Krebs cycle NH3 H2O CO2 Simple products 29 Overview of Catabolic Pathways Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (a) AEROBIC RESPIRATION (b) ANAEROBIC RESPIRATION Glycolysis Glucose (c) FERMENTATION Glycolysis (6 C) ATP Glucose Glycolysis (6 C) ATP NADH NADH 2 pyruvate (3 C) CO2 CO2 Acetyl Co A 2 pyruvate (3 C) CO2 Fermentation Acetyl Co A FADH2 (6 C) ATP NADH 2 pyruvate (3 C) Glucose FADH2 Krebs NADH CO2 Krebs CO2 Lactic acid Acetaldehyde NADH ATP Electrons Electron transport O2is final electron acceptor. Maximum ATP produced = 38 ATP Electrons Ethanol +CO2 Or other alcohols, acids, gases Electron transport Nonoxygen electron acceptors (examples: SO42–, NO3–,CO32–) Maximum ATP produced = 2 – 36 An organic molecule is final electron acceptor (pyruvate, acetaldehyde, etc.). Maximum ATP produced = 2 30 Electron Transport and Oxidative Phosphorylation • Final processing of electrons and hydrogen and the major generator of ATP • Chain of redox carriers that receive electrons from reduced carriers (NADH and FADH2) • ETS shuttles electrons down the chain, energy is released and subsequently captured and used by ATP synthase complexes to produce ATP – Oxidative phosphorylation 31 The Formation of ATP and Chemiosmosis • Chemiosmosis – as the electron transport carriers shuttle electrons, they actively pump hydrogen ions (protons) across the membrane setting up a gradient of hydrogen ions – proton motive force • Hydrogen ions diffuse back through the ATP synthase complex causing it to rotate, causing a 3-D change resulting in the production of ATP 32 Photosynthesis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. • Occurs in 2 stages: • Light-dependent – photons are absorbed by chlorophyll, carotenoid, and phycobilin pigments – Water split by photolysis, releasing O2 gas and provides electrons to drive photophosphorylation – Released light energy used to synthesize ATP and NADPH Glucose H2O ATP 2H + e2 NADPH O2 Chloroplast CO2 33 Photosynthesis Reactions Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (a) A cell of the motile alga Chlamydomonas, with a single large chloroplast (magnified cutaway view). The chloroplast contains membranous compartments called grana where chlorophyll molecules and the photosystems for the light reactions are located. Flagellum Nucleus Chloroplast Cell wall A Stroma B N Granum N Mg N D N C (b) A chlorophyll molecule, with a central magnesium atom held by a porphyrin ring. Photons (c) The main events of the light reactions shown as an exploded view in one granum. 2 2 e– NADP 5 P700 1 photolysis 1/2 O2 2 e– H+ 3 H+ H+ H 2O NADPH Photosystem I P680 2H+ Photosystem II Thylakoid membrana H+ ADP + Pi 6 ATP H+ ATP synthase Proton pump 1 When light activates photosystem II, it sets up a chain reaction, in which electrons are released from chlorophyll. 2 These electrons are transported along a chain of carriers to photosystem I. 3 The empty position in photosystem II is replenished by photolysis of H2O. Other products of photolysis are O2 and H+. 4 Pumping of H into the interior of the granum produces conditions for ATP to be synthesized. 5 The final electron and H acceptor is NADP, which receives these from photosystem I. 6 Both NADPH and ATP are fed into the stroma for the Calvin cycle. H+ Calvin Cycle 2 e– Interor of granum 4 H+ 34 Controlling Microorganisms • Physical, chemical, and mechanical methods to destroy or reduce undesirable microbes in a given area (decontamination) • Primary targets are microorganisms capable of causing infection or spoilage: – – – – – – Vegetative bacterial cells and endospores Fungal hyphae and spores, yeast Protozoan trophozoites and cysts Worms Viruses Prions 35 Relative Resistance of Microbes • Highest resistance – Prions, bacterial endospores • Moderate resistance – – – – Pseudomonas sp. Mycobacterium tuberculosis Staphylococcus aureus Protozoan cysts • Least resistance – – – – Most bacterial vegetative cells Fungal spores and hyphae, yeast Enveloped viruses Protozoan trophozoites 36 Terminology and Methods of Control • Sterilization – a process that destroys all viable microbes, including viruses and endospores • Disinfection – a process to destroy vegetative pathogens, not endospores; inanimate objects • Antiseptic – disinfectants applied directly to exposed body surfaces • Sanitization – any cleansing technique that mechanically removes microbes • Degermation – reduces the number of microbes through mechanical means 37 Practical Concerns in Microbial Control Selection of method of control depends on circumstances: • Does the application require sterilization? • Is the item to be reused? • Can the item withstand heat, pressure, radiation, or chemicals? • Is the method suitable? • Will the agent penetrate to the necessary extent? • Is the method cost- and labor-efficient and is it safe? 38 Antimicrobial Agents’ Modes of Action Cellular targets of physical and chemical agents: 1. The cell wall – cell wall becomes fragile and cell lyses; some antimicrobial drugs, detergents, and alcohol 2. The cell membrane – loses integrity; detergent surfactants 39 Methods of Physical Control 1. 2. 3. 4. 5. Heat – moist and dry Cold temperatures Desiccation Radiation Filtration 40 Chemical Agents in Microbial Control • Disinfectants, antiseptics, sterilants, degermers, and preservatives • Some desirable qualities of chemicals: – – – – – – Rapid action in low concentration Solubility in water or alcohol, stable Broad spectrum, low toxicity Penetrating Noncorrosive and nonstaining Affordable and readily available 41 Germicidal Categories 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Halogens Phenolics Chlorhexidine Alcohols Hydrogen peroxide Aldehydes Gases Detergents & soaps Heavy metals Dyes Acids and Alkalis 42 Principles of Antimicrobial Therapy • Administer a drug to an infected person that destroys the infective agent without harming the host’s cells • Antimicrobial drugs are produced naturally or synthetically 43 Mechanisms of Drug Action Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 4. Protein synthesis inhibitors acting 1. Cell wall inhibitors Block synthesis and repair Penicillins Cephalosporins Vancomycin Bacitracin Monobactams/carbapenems Fosfomycin Cycloserine Isoniazid on ribosomes Ribosome Site of action 50S subunit Chloramphenicol Erythromycin Clindamycin Streptogramin (Synercid) Substrate 2. Cell membrane Enzyme Cause loss of selective permeability Polymyxins Product 3. DNA/RNA Inhibit replication and transcription Inhibit gyrase (unwinding enzyme) Quinolones (ciprofloxacin) Inhibit RNA polymerase Rifampin Site of action 30S subunit Aminoglycosides Gentamicin Streptomycin Tetracyclines Both 30S and 50S mRNA DNA Blocks initiation of protein Synthesis Linezolid (Zyvox) 5. Metabolic pathways and products Block pathways and inhibit Metabolism Sulfonamides (sulfa drugs) Trimethoprim 44 Antibacterial Drugs that Act on the Cell Wall • Beta-lactam antimicrobials - all contain a highly reactive 3 carbon, 1 nitrogen ring • Primary mode of action is to interfere with cell wall synthesis • Greater than ½ of all antimicrobic drugs are betalactams • Penicillins and cephalosporins most prominent betalactams ß-Lactams: Mechanisms of Action and Resistance https://www.youtube.com/watch?v=qBdYnRhdWcQ 45 Antimicrobial Drugs That Affect the Bacterial Cell Wall • Most bacterial cell walls contain peptidoglycan • Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse • Active on young, growing cells • Penicillins that do not penetrate the outer membrane and are less effective against gram-negative bacteria • Broad spectrum penicillins and cephalosporins can cross the cell walls of gram-negative bacteria 46 Penicillin and Its Relatives Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. • Large diverse group of compounds • Could be synthesized in the laboratory • More economical to obtain natural penicillin through microbial fermentation and modify it to semi-synthetic forms • All consist of 3 parts: – Thiazolidine ring – Beta-lactam ring – Variable side chain dictating microbial activity Nucleus (Aminopenicillanic acid) R Group Betalactam Thiazolidine S CO N CH3 CH3 N O Nafcillin COOH S CH N CO CH3 CH3 COONa N O COOH S Ticarcillin Cl S CO N CH3 CH3 N O N O COOH CH3 Cloxacillin S CH CO N CH3 CH3 COONa Carbenicillin N O COOH Cephalosporins • 4 generations exist: each group more effective against gram-negatives than the one before with improved dosing schedule and fewer side effects – First generation – cephalothin, cefazolin – most effective against gram-positive cocci and few gramnegative – Second generation – cefaclor, cefonacid – more effective against gram-negative bacteria – Third generation – cephalexin, ceftriaxone – broadspectrum activity against enteric bacteria with betalactamases – Fourth generation – cefepime – widest range; both gram- negative and gram-positive 48 Non Beta-lactam Cell Wall Inhibitors • Vancomycin – narrow-spectrum, most effective in treatment of Staphylococcal infections in cases of penicillin and methicillin resistance or if patient is allergic to penicillin; toxic and hard to administer; restricted use • Bacitracin – narrow-spectrum produced by a strain of Bacillus subtilis; used topically in ointment • Isoniazid (INH) – works by interfering with mycolic acid synthesis; used to treat infections with Mycobacterium tuberculosis 49 Antimicrobial Drugs That Disrupt Cell Membrane Function • A cell with a damaged membrane dies from disruption in metabolism or lysis • These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes • Polymyxins interact with phospholipids and cause leakage, particularly in gram-negative bacteria • Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage 50 51