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Microbiology: Introduction to Virology (Pellett) VIRUSES: General: Infectious, obligate intracellular parasite Genome consists of DNA or RNA Metabolically inert on their own (outside the context of a living cell) Viral genome directs its own replication using cellular systems in a host cell Virus particles (virions) are formed by assembly from newly synthesized components within the host cell A progeny virion is the vehicle of transmission of the genome to the next host cell/organism (disassembly initiates the beginning of the next infectious cycle) o This disassembly stage is a vulnerable state for the virus Properties of a Virus: Minimal Virus: genome with origin of replication and a coat o DNA or RNA genome o Proteinaceous coat: also called a capsid Nucleocapsid: genome + capsid Envelope: viruses can be enveloped or not Virion: a complete virus particle with its DNA or RNA core and protein coat as it exists outside the cell; also called a viral particle Translation Parasites: must use cellular ribosomes in a host in order to replicate Classification: Nature of Genetic Material: o RNA: Single or double stranded Positive or negative sense (Baltimore system) At some point in their replication cycle, all viruses must adopt a form that allows transcription of mRNA that can be translated by cellular ribosomes Requires –ssRNA or dsDNA/dsRNA in order to translate into +mRNA Possible Scenarios: o +ssRNA Virus –ssRNA +mRNA o +ssRNA Virus –ssDNA dsDNA +mRNA Non-segmented or segmented o DNA: Single or double stranded Linear or circular Capsid Structure: o Helical o Icosahedral o Complex Other: o Gene organization o Mode of replication o Susceptibility to physical and chemical agents (for example, chloroform makes enveloped viruses non infectious) o Cell tropism (what cells and tissues they infect) o Pathogenic effects MAJOR CRITERIA: o DNA or RNA genome RNA Virus Examples: polio virus, influenza virus DNA Virus Examples: adenovirus, herpesvirus o Nature of capside o Enveloped or non-enveloped (naked) Virion Structure: In general: most viruses smaller than most bacteria Virion: complete infectious form of the virus particle o Capsid: encapsulates the genome; in some cases, surrounded by an envelope (derived from host cell membranes) Helical: enveloped Icosahedral: enveloped or non-enveloped Complex o Non-Structural Proteins: Enzymes Host regulators Individual virus species may share many properties with their relatives, but yet still have readily distinguished genomes: example of differences between herpesviruses shown via Southern blot Examples: o Picornaviruses: Small Non-enveloped +RNA genome (needs to be transcribed to negative sense) Non-segmented: genome encodes single open reading frame that is translated into a large polypeptide and then proteolytically processed to a set of individually functioning proteins o Influenza Viruses: Enveloped -RNA genome Segmented: each gene encoded on individual chromosomes; basis for reassorment (new strains of virus emerge from infections with 2 different strains) o Adenovirus: Non-enveloped dsDNA genome Transcribed by cellular RNA polymerase II (studying this virus led to discovery of mRNA splicing) o Herpesvirus: Enveloped Tegument: layers of proteins between envelope and capsid Important in helping the virus control the cell following infection dsDNA genome (may encode for as many as 200 genes; tightly controlled expression) Properties of Lytic Infections: Lytic Infection: making new infectious virions; can be initiated by a single virion o Eclipse Period: interval between disassembly of input virion and production of new infectious progeny o Burst Size: number of infectious virions released per infected cell (100s-1000s) o Time Scale: can be hours or days from time of infection to lytic burst Steps: o Entry: attachment to receptor, penetration and uncoating Mechanisms: Endocytosis (poliovirus, influenza virus, adenovirus) Genome injection (poliovirus) Fusion at cell membrane (HIV, vaccinia virus, herpesvirus) o Gene Expression: mRNA synthesis Protein translation o Genome replication Sites: Cytoplasm: most RNA viruses + poxviruses Nucleus: most DNA viruses + orthomyxoviruses Both: retroviruses, hepadnaviruses o Assembly/packaging o Egress/release Mechanisms: Cell lysis (poliovirus, adenovirus) Budding from cytoplasmic membrane (influenza, HIV) Cell associated (vaccinia virus) Vesicle fusion (herpes virus) Consequences of Infection: Transformation: o Immortalization - o Serum independent cell replication o Loss of contact inhibition o Ability to form tumors Cytopathic Effect (CPE): o Rounding (lose defined shaped) o Fusion (syncytia formation- giant infected cell) o Intracellular vacuoles and inclusion bodies o Lysis o Cell death Introduction to Virology II: Pathogenesis General: Most result in asymptomatic (subclinical) infections Same disease may be caused by a variety of different viruses Same virus may cause a variety of diseases Outcome of infection determined by the interaction of the virus and the host o Virus strain o Route of infection o Infectious dose o Host immune status o Host genetics o Virus cytotoxicity o Immunopathology o Host health o Co-infections Local vs. systemic infections Seasonality Various incubation periods: time to disease Principles of Viral Infections: Modes of Transmission and Host Entry: o Person-to-person transmission: some paths more likely if illness present; others if relatively healthy Fecal-oral Respiratory Animal bite Arthropods Sexual Bloodborne Vertically (transplacental, genetic) o Virus can enter and egress from the same or different routes: some also use multiple paths o Defenses at portals of entry: keratinized skin, mucosa Sites of Primary Replication Modes of Intrahost Spread: via blood, lymphatic ducts, or neurons (cell-free or cell-associated) Sites of Secondary Infection Organs and Tissues Affected Host Responses: Clearance vs. Persistence: o Latent State: Cellular: no infectious particles produced; can be reactivated to lytic state Organismal: period between infection and disease o Persistent Infection: Cellular: lytic state, equilibrium between cell death and production (but still making virus paticles) Organismal: continuous inhabitation of the host o Abortive Infection: non-productive, not reactivation Patterns of Viral Infection: o Acute: GI viruses o Latent: HSV (reactivations occur) o Progressive: HIV or hep C o Chronic or Persistent: HIV or hep C o Failure to clear all evidence of infection: polio and measles o Subclinical/asymptomatic: ~50% of HSV transmission is during asymptomatic periods o Slow: long-term persistence prior to onset of disease (HPV and cervical cancer) Viral Pathogenesis: Genes groups based on contribution to virulence: o Basic Replication Functions: viral RNA polymerase o Immunevasion: proteins that downregulate Ag presentation o Cell and tissue tropism: HIV uses CD4 as cellular receptor o Toxic products: rotavirus NSP4 induces diarrhea Viral load matters: the larger the load, the higher the probability of disease Viruses and Cancer: generally unintended by-products of niche-management by the virus o HPV and cervical cancer o HTLV-1 and T cell leukemia o HHV-8 and Kaposi’s sarcoma o EBV and Burkitt’s Lymphoma and nasopharyngeal carcinoma o Hep B/Hep C and liver cancer Host Responses: Innate immunity: o Physical barriers: skin, mucosa, respiratory filters o Intracellular defenses: IFN (and other cytokines), PKR, RNase, stress responses, cell-death (apoptosis, necrosis, autophagy) o NK cells, macrophages and neutrophils Acquired immunity: o Antibodies and complement Abs against virions: neutralization Abs against viral proteins on cell surfaces: neutralization, inhibition of viral replication, inhibition of virus release, infected cell lysis and clearance, inhibition of cell-cell transmission o T cells Immunopathology: o Systemic responses to IFN o Inflammation o Immune complexes o Immunocytopathology ESSENTIALLY EVERY DEFENSE CAN BE BLOCKED OR CIRCUMVENTED BY A VIRUS Immune Evasion: All viruses do it (especially large DNA viruses) Many viral immunomodulatory genes are host-derived Targets for immune evasion: o Innate Defenses: Apoptosis IFN responses PKR pathway (proten kinase RNA-activated pathway): activated by dsRNA, which is uncommon outside of a virus infection and net result is translational arrest (under normal conditions); the virus can employ mechanisms to inhibit this pathway (allowing translation to occur) o Adaptive Responses: Ag prensetation Laboratory Diagnosis of Viral Infections: Detect the Agent: o Cytology o Electron microscopy o Direct fluorescent Ab (DFA) o Cell culture o Nucleic Acids (PCR) Detect Response to the Agent: o Serotology (look for Abs against the agent) Antivirals: Must selectively inhibit viral functions without damaging the host o Targets: every step in replication cycle is potential target Attachment and entry (fusion inhibitors) Uncoating (ion channel blockers) Genome replication (polymerase inhibitors) Protein synthesis/assembly and maturation (protease inhibitors) Egress and release (neuraminidase inhibitors) Relatively ineffective clinically as compared to bacterial agents o Why? Many rounds of viral replication has occurred during the incubation period before symptoms develop Vaccination is most important to prevent infection Key Issues: o Specificity o Toxicity o Rapid diagnosis o Therapeutic threshold o Resistance