Microbiology BIO 3713
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Mr. Uriel Harvey
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This 8 page Class Notes was uploaded by Mr. Uriel Harvey on Thursday October 29, 2015. The Class Notes belongs to BIO 3713 at University of Texas at San Antonio taught by Floyd Wormley in Fall. Since its upload, it has received 20 views. For similar materials see /class/231361/bio-3713-university-of-texas-at-san-antonio in Biology at University of Texas at San Antonio.
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Date Created: 10/29/15
Virology Review Characteristics ofViruses gt Nonliving entities 39 Not considered organisms gt Can infect organisms ofevery domain 39 All life forms gt Commonly referred to by organism they infect 39 ie bacteriophage Virus architecture gt Virus particle called VI n gt Consists of nucleic acid surrounded by protein coat 39 Protein coat termed M 0 Ca psid composed of caEsomers gt Viruses have different shapes 39 Isometric o Composed offlat surfaces with equilateral surfaces 0 lcosahedral 1 L hquot quot 39 39 Helical o Gives virion a helicle or rodlike appearance 39 Most phages are Eleomorghiclcomglex o Isometric head w long helical sheath ortail Virus architecture gt Shape determined by the size and shape of protein capsid spherical or helical gt Nucleocapsid 39 Viral capsid together with the nucleic acid that is packed wn the protein coat gt Attachment proteins or spikes and tailfibers 39 Mediate attachment to host gt Two types of virion 39 Naked without envelope 39 EnveloEed surrounded by lipid membrane which may contain matrix proteins Viral genome gt Contains only single type ofnucleic acid 39 Either DNA or RNA 0 NEVER BOTH gt Can be linear or circular gt Single stranded ordouble stranded Replication cycle overview Only multiply inside metabolizing cell 39 obligate inh39acellular parasite 39 Use host machinery to support reproduction gt Evenvirus contains information to encode proteinsfor 39 viral protein coat 39 assure replication ofviral nucleic acid 39 movement in and out of host cells 39 Needed enzymes not present in infected cell gt Viruses live in two phases 39 Extracellular phase 0 Metabolicallyinert 39 Intracellular phase 0 Metabolically active Phage Interactions with Host Ces gt Effect on cells depends on infecting phage 39 Productive Infection some phage multiply inside cell producing numerous progeny o Lytic cycle 0 Phage lyses infected cell 0 Phages take over cellular metabolic processes o Nonlytic cycle 0 Phage leaks of extrudes out of infected cell 0 Phages only partially take over cellular metabolic processes Latent Infection little or no apparent sign of infection gt Bacteria carrying the phage DNA is called a lysogen 39 Lysogenic state some phage integrate into host genome orthe DNA replicates as a plasmid itemperate phages 39 Phage DNA can often code for proteins that modify the properties of the bacterium Lysogenic conversion 0 toxin production in pathogenic bacterial strains The six stages of lytic phage replication by dsDNA phages gt Attachment gt Penetration gt Transcription gt Replication gt Assemblyor maturation gt Release Lysogenic state phage replication in a latent state gt Most phages 90 are temperate phages gt Can occur in slow growing bacteria 39 Phage DNA becomes integrated into bacterial genome 0 Integrated phage DNA referred to asgroghgge 0 Bacterial cell carwing prophage is a lysogenic cell or lysogen o Phage DNA oftentimes code for proteins that modifythe properties of a cell lysogenic conversion me temperate phages multiply as plamids wn cell gt Lysogeny begins like the lytic cycle 39 Attachment 39 Penetration then 39 Incorporation Transduction gt Process in which DNA is transferred from one bacterial cell the donor to another the recipient cell gt Generalized Transduction 39 Carried out by generalized transducing phages o Virulent and temperate phages gt Specialized transduction 39 Carried out by specialized tranducing phages o Onlytemperate phages Host Ranges of Phages gt Numberof different bacteria that phage can infect termed host range 39 Usually limited to single bacterial species for a single phage gt Factors limit host range 39 Two most important 0 Phage must be able to attach to host receptors 0 Must overcome restrictionmodification system ofthe host cell Receptors on bacterial surface gt Vaw in chemical structure and location 39 Usually on bacterial cell wall gt Sites can be altered by two mechanisms 39 Receptor sites can be altered by mutation 39 Lysogenized bacteria can alter cell surface 0 Results in alteration of receptor site Restrictionmodi cation system gt Bacteria have gt Restriction enzyme that codes for endonuclease quot fur en yme of 39 Cuts small segments of DNA 0 May recognize viral DNA and cut out gt Modification 39 39 39arnllntn nN recognized by restriction enzyme 39 Methylated bases not recognized by restriction enzyme 0 Protects bacterial cells own DNA v Animal Viruses with Hosts gt Reproductive cycle of animal virus can be compared to virulent bacteriophage 39 Essential steps include 0 Attachment 0 Entw into susceptible cell Targeting site of reproduction cyto nucleus etc Uncoating of virion O Removing protein coat exposing nucleic acid Replication of nucleic acid and protein Matu ration Cell lysis Spreading within host Shedding outside host 0 Transmission to next host gt Envelope of the enveloped virion and the plasma membrane ofthe host may fuse orthe virion may be taken intothe cell by gt m by 39 39 39 39 WlLl Ll 39 Naked virionsdissolvesthe vesicle for release ofthe nucleocapsid intothe cytoplasm gt quotquot quot 39 39 in cytoplasm u nuueu 39 quot gt Most cells die due to take overof host cell machinery by virus orfrom the release of enzymes contained wn host lysosomes 39 No host cell protein or nucleic acid production occurring 39 Some viruses encode Iytic enzyme gt C opathic effects of cells due to dead cell lysis and the release ofvirions gt Enveloped viruses obtain there envelopes asthey exit 39 Plasma membrane Nucleus ER Golgi apparatus gt Enveloped viruses budding from the 39 39 g 39 39 g Iu ion of gt Budding may not lead to cell death v Stages ofthe viral growth cycle 39 g mum with the plasma membrane gt Attachment and penetration by parental virion 39 Membrane fusion endocytosis followed by membrane fusion endocytosis followed by escape from vessicle naked viruses gt Uncoating ofthe viral genome Nucleic acid is released into the cytoplasm or the nucleus gt Early viral mRNA and protein synthesis 39 Early proteins are enzymes used to replicate viral genome gt Viral genome replication gt Late mRNA and protein synthesis 39 Structural capsid proteins gt Progenyvirion assembly gt Virion release from the cell v RNA Virus Replication gt No viral proteins can be made until viral messenger RNA is available Thus the nature ofthe genome in the virion affects the strategy of the virus v Plusstranded RNA viruses gt The virion RNA is the same sense as mRNA and so functions as mRNA This mRNA can directly be translated into proteins immediately upon infection of the host cell 39 Examples 0 poliovirus picornavirus o togaviruses flaviviruses Negativestranded RNA viruses The virion RNA is 39 LU mRNA and be copied into the complementaw plussense mRNA before proteins can be made Thus the virion must carry along with it an RNAdependent RNApolymerase sothat they can make mRNAs upon entering the cell gt Examples 39 influenza virus orthomyxovirus 39 measles virus mumps virus para myxoviruses o 0 o 00 o 00 rabies virus rhabdovirus Doublestranded RNA viruses gt The virion RNA is double stranded and so cannot function a mnmA mu u 39 39 RNApolymerase so that they can make mRNAs upon enteringthe cell 39 Example gwimitanm39 quot 4 quot rotaviruses belong to reovirus family RNA viruses that copy leir RNA to DNA gt Retroviruses 39 Theirvirion RNA although plussense does not function as mRNA immediately on infection since it is not released from the capsid into the cytoplasm Instead it senes as a template for reverse transcriptase and is copied into DNA Reverse transcriptase is not available in the cell and so these viruses need to code for this enzyme and bring it along with it upon infection ofthe cell Retroviruses Contains 2 copies of ssRNA and Reverse Transcriptase Hepatitis B has an RT as well ssRNA converted to dsDNA by RT no proof reading dsDNA is integrated into host genome as a provirus Infection may be latent or productive Viral DNA is transcribed by host RNA polymerase into a polycistronic mRNA mRNA molecule is translated into a long polyprotein VVVVVVV Polyprotein is cleaved by a viralencoded protease to yield the individual proteins that will eventually make up the virion 39 Protease is target of protease inhibitors Viral Genetic Alterations gt Genetic reassortment 39 Genetic ilu e le ulL flum Lhe same cell 0 Each virus incorporates segments of viral DNA 0 One segment comes from one virion 0 Rest of segments come from othervirion Reassortment responsible for antigenic shift in Influenza virus May lead to change in viral surface hemagglutinin expression and inability of antibodies to recognize new influenza strain 0 Loss of herd immunity leadingto past and perhaps future pandemics Viruses can also alter properties via point mutations 0 Example Antigenic drift of influenza 0 RNA dependent RNA polymerase has no proof reading ability leading to possible mistakes DNA Virus Replication General DNA Virus Replication Strategies gt The virus needs to make mRNAs that can be translated into protein bythe host cell translation machinery gt The virus needs to replicate its genome gt Host enzymes for mRNA synthesis and DNA replication are within the nucleus except forthose in mitochondrion Therefore ifa DNA virus is to avail itself ofthese enzymes it needsto enterthe nucleus Production of viral mRNAs and proteins gt Gene expression is divided into early and late phases 39 Early genes encode enzymes and regulatory proteins needed to startviral replication processes Late genes encode structural proteins proteins needed forassembly of the mature virus Viral mRNA gt Viral mRNAs have A methylated GTP cap 39 A polyAtail 39 mRNA generated by splicing gt Some viruses make more than one type of RNA from one piece of DNA done by shifting of the reading frame gt Some DNA viruses exercise temporal control of transcription 39 Repressor protein prevents transcription of some genes until later gt Different processes are used to generate the monocistronic mRNAsthat will code for a single protein from the polycistronic viral genome 39 Individual mRNAs are transcribed by pacific initiation adenn iru e and the tumor viruses Genome may be segmented into multiple pieces each coding for a single mRNA reoviruses and influenza viruses o 00 39 Entire genome istranslated into one long polypeptide which is then cleaved into specific proteins by a protease polioviruses gt Naked virions 39 The cell may lyse and release the virions orthe virions may be released by exocytosis gt Enveloped virions 39 Newly formed quotnakedquot quotclothingquot en elupe uuuugn 39 39 39 nuclear membrane or cytoplasmic tearing off a piece of the host cell lipid bilayer as it exits 39 Virus specific proteins enter cell membrane at specific sites 39 Viral nucleocapsid interacts with the specific membrane site mediated by matrix protein Classi cation of animal viruses Taxonomic criteria based on 39 Genomic structure 0 DNA or RNA 0 Singlestranded ordoublestranded 39 Virus particle structure 0 Isometric o Pleomorphic o Helical 39 Presence or absence of envelope enveloped vs naked Interactions ofAnimal Viruses with their host Persistent infections latent chronic or slow gt Latent infections 39 Infection is followed by symptomless period then reactivation 39 Infectious particles not detected until reactivation 39 Symptoms of reactivation and i tial disease may differ 39 Example Herpes simplex viruses 1 and 2 HSV1 and HSV2 o Shingles zoster Chronic infections gt Infectious virus can be detected at all times gt Disease may be present or absent during extended times or may develop late gt Best known example 39 Hepatitis B aka serum hepatitis Slow infec ons long period oftime 39 No sign ifica nt sym ptoms a ppa rent d u ring this time gt Two groups of infectious agents cause slow infections Retroviruses which include HIV a Lentivirus 39 Prionsslow virus disease Viruses and Human Tumors gt There are two classes of tumor viruses 39 DNA tumorviruses 39 RNA tumorviruses RETROVIRUSES gt Ifa virus takes up residence in a cell and alters the properties of that cell the cell is said to be transformed gt Tumor viruses interact with host cells in one of two ways 39 Virus can go through productive cycle and lyse cell 39 Virus can transform cellwithout killingit gt Cancers caused by viruses can result from 39 Encoding proteinsthat promote uncontrolled cell growth stimulation of signal transduction pathwaysthat regulate cell growth 39 Integration of viral oncogenes causes malignant transformation of normal cells into cancer cells into host DNA HTLVl 39 Activation of host cell protooncogenes involved in host cell growth regulation by integrating into a key regulatory area Methods of Studying Viruses Quantitation Plaque assay 39 Determines numberofviruses in solution o a o 00 0 Known volume of solution added to actively metabolizing cells 0 Infection lyses cells and leadsto clear zone or plaque surrounded by uninfected cells 0 Fluid is removed and an agaroverlay is added stops lyses o Stain is added to bettervisualize plaques 39 Each plaque represents one virion o Plaques are only produced by infected cells Hemagglutination gt Some animal viruses clump or agglutinate with red blood cells 39 Termed hemagglutination gt The quot39 quot quot 39 39 Other Infectious Agents Prions agglutination is titerof the virus gt Proteinaceous infectious particles gt Linked toa numberoffatal human diseases 39 All afflictions cause brain degeneration 0 Brain tissue develops sponge like holes 0 Disease termed transmissible spongiform encephalopathies 39 Symptoms may not appearforyears after infection gt Apparently arose following gene encoding normal prion protein gt Mutation caused protein to have different folding properties gt Mutated protein resistant to proteases 39 Normal protein sensitive gt Normal proteins and Prions are Resistant to UV light and nucleases 39 Due to lackofnucleic acid gt Inactivated by chemicals that denature proteins Viroids gt Define group of pathogens much smaller and distinctly different from viruses gt Consist solely of small single stranded RNA molecule gt Vaw in size gt Have no protein coat 39 Allowsthem to be resistant to proteases gt Otherviroid properties include 39 Replicates autonomously in susceptible cells 39 Single viroid capable ofinfectinga cell 39 Viroid RNA is circular and resistant to nuclease digestion gt All identified viroids infect plants 39 Diseasesinclude 0 Potato spindle tuber o Chrysanthemum stunt o Cadangcadang Mechanisms of Action of Antiviral Drugs A successful antiviral will Interfere with a virusspecific function 39 Function is unique to the virus 39 The similar host action is much less susceptible to the drug gt Interfere with a cellular function so that the virus cannot replicate Hope is that this will only kill virally infected cells gt Toxicity may be acceptable ifthere is no other alternative 39 Betterto have a little toxicity than to be dead Available antiviral drugs effective against speci c type of virus None eliminate latent virus Potential targets include gt gt Viral uncoating gt Transcription of viral genome 39 Polymerases V 39 mRNA transcription 39 mRNA processingpolyA capping splicing Translation to proteins Posttranslational modification of proteins Assemby Attachment and Entry of HIV gt For HIV to infect a cell it must bind both to CD4 antigen and to a coreceptor a chemokine receptor CCRS or CXCR4 E gt Enfuvirtide Other namesDP178 pentafuside T20 Fuzeon 39 Peptides derived from gp41 can inhibit infection probably by blockingthe interaction of gp41 with cell membrane proteins duringfusion U by Lapping 39 39 39 g min re uu uum 39 two gp41 39 39 39wl39 is necessawfor fusion Enfuvirtide Fuzeon is a 36 amino acid peptide that corresponds to residues 127162 of gp41 and blocks this conformational change gt Maraviroc Brandnames Selzentry orCelsentri outside the US 39 Approved for use in HIVinfected patients in August 2007 It blocks the interaction between chemokine receptor CCR5 and HIV gp120 Because HIV can also use anothercoreceptor CXCR4 an HIV tropism test is performed to determine ifthe drug will be effective Viral uncoating Arildone and the WIN compounds 39 Inhibits uncoating of picornaviruses eg poliovirus rhinovirus Pleconaril 39 A derivative of WIN compounds that interrupts the replication ofthe virus by stoppingthe shedding of nucleocapsid proteins from the RNA 0 Active against a variety of entero and rhinoviruses icornaviruses Amantadine and Rimantadine 39 Similar in chemical structure and mechanism of action 39 Mode of action 39 in lmnu A 39 39 t it enters cell 39 Prevents severity and duration ofdisease 39 Good alternative to vaccine in immune compromised and elderly patients 39 Resistance develops frequently and may limit effectiveness of drug Nucleic acid synthesis gt Antiviral drugs that blockviral nucleic acid synthesis are selective because 39 Virus can use its own enzyme to activate drug 39 Viral polymerases are much more sensitive to the drug than the corresponding host enzymes gt Virus activates these drugs within the cell while the uninfected cells are usually left alone gt Most nucleic acid synthesis inhibiting drugs are nucleoside analogs with an altered sugar base or both Nucleo de gt Base 5carbon sugarribose or deoxyribose id phosphate group Nucleoside gt Base 5carbon sugarribose or deoxyribose butno phosphate group Nucleoside analogs gt Similarin structure to nucleoside gt 39 39 become 39 quot 39 gt Incorporation of analog results in termination of growing nucleotide chain chain terminators or a defective strand with altered base pairing properties gt Examples of nucleoside analogs 39 Acyclovir Valaciclovir Penciclovir Famciclovir Ganciclovir 39 Ribava rin 39 Zidovudine AZT 39 DidanosineDDI 39 Lamivudine3TC gt Agclovir DNA synthesis inhibitor 39 Drug is phosphowlated specifically by herpes sim glex virus thmidine kinase to an active form which then blocks DNA syn lesislchain terminator by inhibitingthe polymerase competitively it binds to the active site of the enzyme o Thymidine kinase of39 39 39 39 39 im all the ilu LU grow in cells that do not have a high concentration of phosphowlated nucleic acid precursors eg nene cells that are not replicating Resting cells do have unphosphowlated nucleosides so by bringing in its own kinase it can grow in nondividing cells 0 Host cells have a thymidine kinase but its kinase is specific only forthymidine unlike the viral one So acyclovir is given in an unphosphowlated form which is more often phosphowlated by the viral thymidine kinase and not the host39s 39 Effective against a variety of herpes infections HSV1 HSV2 Va ricellaZosterVirus HS keratitis fever blisters and genital herpes Other DNA syntheses In s gt Penciclovir 39 Similar in action to acyclovir in that is it is a chain terminator It can only be used as a topical cream because of insolubility 39 Used against HSV1 and 2 and VZV gt Famciclovir 39 Prodrug of Penciclovir and is converted to Penciclovir 39 Soluble in water and can be administered orally 39 It is also used for HSV1 and 2 and VZV infections gt Ganciclovir DNA synthesis inh 39 Similarto acyclovir exceptthe structure has been changed making it active against CMV cytomegalovirus which doesn39t encode forthymidine kinase 0 Ganciclovir is phosphowlated by a CMVencoded protein kinase UL97 which accounts for its specificity for infected cells 0 Selectivity is also achieved because the viral polymerase has 30 times greater affinity for Ganciclovirthan the host nzyme Used predominantly for CMV ret s in AIDS patients Nucleoside inhibitors of reverse transcriptase RT AZT DDI nnr gt Reverse transcriptase RNA dependent DNA polymerase is more sensitive to the drug than human DNAdependent DNA polymerase but toxicity is still high gt Resistant viral mutants rapidly occurs gt Drugs oftentimes used in combination therapies Nonnucleoside reverse transcriptase in ibitors gt Inhibits activity of reverse transcriptase by binding to site other than nucleotide binding site gt Work against nucleosideanalog ie AZT DDI and DDC resistant HIV with minimal toxicity gt Rapid development of drug resistant HIV strains gt Drugs used in combination with nucleoside inhibitors and protease inhibitors 39 Examples nevirapine delavirdine atenidine efavirenz Nonnucleoside DNA polymerase inhibitor gt Fosca rnet 39 Competitive inhibitorof DNA polymerase 39 Herpes DNA polymerase inhibited at 10100X lowerconcentration than cell DNA polymerase giving some selectivity Protease inhibitors gt Inhibit HIV encoded enzyme protease 39 Enzyme essential for production ofviral particles 39 Examples indinavir and ritonavir 0 Used in treatment of HIV 0 Monotherapy leadsto rapid resistance lntegrase In bitor gt Inhibit HIV encoded enzyme integrase gt Raltegravir sentress gt sentress can be used as part ofa HAART regimen when the patient is resistant to other drugs such as protease inhibitors gt It is not approved for HIVinfected children Highly Active AntiRetroviral Therapies HAART gt Combination therapy consisting of AZT lamivudine 3TC and protease inhibitor 39 Other nucleoside nonnucleotide or integrase inhibitors can be substituted into regimen gt Therapy can drive down HVto undetectable levels gt Must be taken as prescribed thus compliance an issue 39 Specific times of day rs
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