Biology III Cell Structure And Function
Biology III Cell Structure And Function BIOL 23100
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Date Created: 09/19/15
LECTURES 40 amp 41 08 amp 10 December 2010 P J Hollenbeck BIOL 231 Cell Biology of Pathogens Reading just a bit pp 12425 22326 Prob exam IV 2005 8 That s the problem with Nature Something s always stinging you or oozing mucus on you Let s go inside and watch TV Calvin amp Hobbes I Pathogens what are they and how do they invade our bodies 1 c a A What are they Pathogens are agents that cause include diseases Human 1 1 other metazoan organisms such as Ascaris a nematode parasite or T aenia solium tapeworm a segmented parasite 2 Singlecelled protozoa such as T oxoplasma gondii 3 Fungi such as yeast or Tinea pedis athlete s foot 4 Bacteria you can probably name a dozen 5 Viruses again you know a lot of these 6 Prions such as bovine spongiform encephalitis mad cow disease we ll come back to these shortly B Most organisms that live in us or on us are NOT pathogens 1 Your body is comprised of approximately 1013 human cells but your typical healthy body load of bacteria fungi and protozoa is approx 1014 cells The vast majority of these live with us and use us for nutrition without adversely affecting our health indeed some play a positive role in our own normal body mctions such as digestion 2 Opportunistic versus dedicated pathogens Opportunistic pathogens take advantage of wounds in the skin deficiencies in the immune system and so on to enter and thrive in the body This puts them in a place where they do not normally reside and can transform them from innocuous or even help ll microbes into diseasecausing agents Dedicated pathogens have evolved highlyspecialized mechanisms for breaching organi smal cellular and biochemical defenses They usually also have the ability to evoke responses from the host that actually enhance pathogen survival C Whether opportunistic or dedicated pathogens must do the following to survive 1 Colonize the host organism Opportunistic pathogens and dedicated pathogens tend to do this in different ways 2 Find a niche in the host compatible with their nutritional and reproductive needs 3 Avoid or subvert the host s immune responses to invasion 4 Replicate themselves using resources of the host 1 5 Spread to a new host repeat the process ltOur body has several lines of defense to prevent pathogens from entering in the first place The epithelial sheets of cells that form our body s boundaiy are our first line of defensegt 6 Many of our epithelia such as lung and GI tract secrete mucus that serves as a physical barrier and also contains factors such as antibacterial peptides Lung epithelia have cilia that constantly sweep the mucus and the bacteria trapped in it out of the airway The GI tract accomplishes the same thing via peristalsis 7 The tight junctions of epithelia help to maintain a barrier to infection 8 Macrophages patrol virtually all tissues of the body and can destroy many pathogens ltOnce they have invaded the host organism some pathogens live in the lumen of an organ others reside in body uids etc Let s concentrate on those pathogens that actually enter the cell and reproduce there As you will see these invaders have taught us a great deal about cell biologygt II Intracellular pathogens A Pathogens with very different properties can infect our cells We ll consider bacteria viiuses and prions These can be viewed on a spectium of how large a toolkit they bring to the host cell 1 Bacteria have their own genome encoding all of the proteins that they need to make new bacteria Thus they bring into the host cell their own machinery for DNA replication transcription protein translation division etc Under appropriate conditions bacterial pathogens can be grown outside of the host in an abiotic medium 2 Viruses are more pareddown pathogens than bacteria They are essentially DNA or RNA a very small genome wrapped in a protective shell of proteins and sometimes membrane They require the cells of their host in order to replicate Some viruses bacteriophage infect bacterial cells 3 Prions are the strangest of all They consist solely of a protein ie they have no genome Exactly how they enter the cell remains a subject of active investigation B How do bacteria and viruses invade cells Intracellular pathogens exploit or hijack so many different elements of the cell s machinery that we can t describe them all in one or two lectures Here we ll consider the basic ways that they enter modify and exploit the cell for reproduction One of the most important themes of microbial pathogenesis is this studying how microbes invade the cell has taught as many of the details of normal cellular pathways 1 Bacteria are very large compared to other cargos so they are taken up by phagocytosis There are two major ways that bacteria induce the cell to engulf them In the zipper mechanism used e g by Listeria bacterial surface proteins have evolved to bind normal cell surface receptors When such bacteria contact the cell surface their binding to many surface receptors causes the cell membrane to surround them and create a phagosome In the trigger mechanism used by eg Salmonella the bacterium contacts the cell injects proteins into the cytoplasm that stimulate actin polymerization and thus induces the membrane to engulf the bacterium Either mechanism generates a phagosome within the cell that contains the bacterium See the figure below 2 Viruses ride several different pathways into the cell Viruses With a membrane envelope can fuse with the plasma membrane eigi HIV or be taken up by endocytosis eigi in uenza Viruses Without membrane envelopes bind various surface receptors and enter via receptormediated endocytosis ergU polio and some retroviruses See the gure below for diagrams of this adhesin receptors integrins cadherins adhesin HOST CELL A IPPER EG i NlSM actin filaments type III secretion apparatus l B W other cytoskeletal effectors EC39H NlS HIV AIDS virus Influenza Vlrus E CYTOSOL CYTOSOL mam T I J m A poliovirus adenovirus CYTOSOL 1 32 nuclear envelope NUCLEUS D C How do bacteria and viruses thrive within cells Pathogens that enter the cell in a phagosome or endosome face a problem unless they can subvert the cell s normal endocytic lysosomal pathway they will end up in the highly acidic degradative environment of the lysosome and then they are history They escape this fate in three basic ways 1 Escape the compartment before being digested all viruses and some bacteria elgl Listeria This means that the whole organism bacteria or just the genome viruses gets across the organelle phagosomal or endosomal membrane and into the cytoplasm 2 Alter the compartment to prevent acidification or fusion with lysosome most bacteria elg Legionella or Mycobacterium tuberculosis and eukaryotic parasites 3 Survive in the hostile environment of the lysosome very rare elg Q fever intracellular pathogen y quot39 ome or 1 i phagosome fusion with lysosomes to form f5 phagolysosome ltA small detour now to consider the most surprising of pathogens prions The demonstration that there were infectious agents that consisted only of protein with NO nucleic acids no genome required decades of contentious research and debate Now we accept readily that Mad Cow Disease for example is a prion disease but this understanding came slowlygt D Prions When proteins fold improperly they can form abnormal aggregates or filaments that damage or kill cells and tissues Mutated or damaged proteins that misfold and form aggregates probably play a role in Alzheimer s and Huntington s diseases for example But what if a misfolded protein could also induce normal copies of itself to misfold This is what we think happens in prion diseases Examples of prion diseases are scrapie sheep bovine spongifonn encephalopathy cows Creutzfeldt Jacob disease and kuru humans 1 The prion protein PrP is a protein of the surface of neurons When it is converted from its normallyfolded form to its improperly folded form it sticks together in large aggregates that are resistant to normal protein degradation In addition improperly folded PrP interacts with normallyfolded PrP and converts it from the normal form to the improperlyfolded aggregating form This allows the aggregated protein to spread from cell to cell and from organism to organism as an infectious agent 4 2 The exact mechanism by which the A very rare conformational change animal to another or to and among humans is not completely clear but 3 new 0 39 n c 39 39 tissue is almost Q Q certainly one avenue The disease that rst brought prions to our attention in V humans was kuru which was prominent among tribes in the highlands of New 7 Guinea It was spread by the ritual consumption of the brains of the dead when this practice was discontinued the disease all but disappeared heterodimer Q 3 The role ofmutation in the prion hcmodimer protein is not clearr Although many I animals With prion disease show speci c 6 mutations in the prion protein others do Q Q not It is poss39 e that a prion pro i q infectious one Mutations may not be 7 m Essnnualccll ml w necessary for the misfolded form to prmem aggregate mm Wquot occur but they may make the transition to the misfolded form more likely 4 As a sign of the transformation of infectious proteins from a crackpot idea to an established 39 T f f 39 39 39 39 a awarded the 1997 Nobel Prize in Medicine It recognized his original seminal work as well as his long ght for its acceptance L E khan III Fighting intracellular pathogens ltOne the triumphs of modern medicine and public health is the control of infectious disease Still there are many intracellular pathogens 39 39 nun i viruses tha ha i t i in attempts to fend them off with drugs before or during infection Why is this so dif cult7gt A Tackling the differences between pathogen and host In order to disrupt the life cycle of an39 39 and kill it with dlu s I at are not essential for the host cell Antirbacterial drugs can be directed against many features of the pathogen such as 1 The cell wallr Our cells don t have these so drugs like penicillin or cephalosporin that inhibit cell wall synthesis can inhibit bacterial reproduction with minimal effect on the host cell or organismi 2 Protein synthesisr Bacteria do not use the host cell s translation machinery furthermore 39 39 quotff L L f r Thus antibiotics like tetracycline or streptomycin which target the smaller 305 bacterial ribosmal subunit and erythromycin or chloramphenicol which target the SOS ribosomal 39 39 39 39 39 rath rthan 5 39 5 3 Other examples pathogenic bacteria can differ from their host cells intheir membrane composition DNA gyrase RNA polymerase and many other molecular features These all serve as current or potential targets for antibacterial drugs B Antiviral drugs Viruses mainly use the enzymatic machinery of the host cell to reproduce so it is much more dif cult to design therapeutic strategies that will disrupt their life cycle once they have entered our cells Viral proteases or reverse transcriptase are available targets in some viruses But the most widespread and successful anti viral strategy vaccination mobilizes our own immune system to prevent frank infection inthe first place Note about opportunistic pathogens They can be part of the host s normal ora that has accessed a bad place say E coli from e gut moving into the peritoneum due to a perforated bowel 1h y can be organisms from the external environment such as Pseudomomzs ueruginosa a gram negative bacterium found ubiquitously in nature An opportunistic P uemginosa infection begins when some fault in normal host defenses a break in the skin for example allows it enter the host organism Although it is not part of the normal ora of any organism it is such a capable opportunistic pathogen that it can grow and reproduce in may tissues and thus it can be responsible for a very wide range of diseases These include dermatitis septicemia urinary tract infections pneumonia and other chronic lung infections endocarditis etc It 39 responsible for many infections acquired in the hospital So naturalists observe a ea Has smaller eas that on him prey And these have smaller still to bite em And so proceed ad infinitumquot Jonathan Swift 1733 log of tlez 7 on mite PATHOGEN GENOME CELL ESCAPING ENTRY ENDOSOME GETTING TO CYTOPLASM bacteria DNA phagocytosis lyse endosome zipper m0dify endosome trigger n0t live in lysosome viruses fusion receptormediated fuse with endosome endocytosis membrane lyse endosome translocate genome across endosomal membrane prions NO 39 39 39 39 lysis or they already reside there
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