Chapter 9
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Chapter 9






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Chapter 9 Presentation Transcript

  • 1. Chapter 9 Outcomes of Infection for the Host
  • 2. Productive Infection
    • Infected cell releases some new viruses
    • Host cell may lyse or may survive for a short period like in HIV-1 or long time like HepB
    • Some virus infections are not productive
      • may be latent infection – genome persists for the cell’s lifetime or pass on to daughter cell
      • may be abortive – neither productive or latent – may be due to a mutation of genome or virus particle may be defective
        • cannot undergo complete replication cycle unless another virus infects the cell to provide the missing function = helper virus, provides good copy of the gene
  • 3. Persistance
    • Virus may persist for long times in the host and are productive like HIV-1 or may persist with periods of latency and productive infection like HSV
    • Some long term infections may cause cancer
    • Some phages including the filamentous phages initiate productive infection of bacterial hosts – appropriate host can shed virus for long periods
  • 4. Effect of Virus on Host
    • Effect on host can range from harmless to deleterious (death)
      • outcome varies on a complex interplay between host, virus and environmental factors
      • hosts have evolved anti-viral defenses with viruses have found ways to evade these mechanisms
    • We will discuss the factors affecting the outcomes of infection
  • 5. Innate Immunity in Vertebrates
    • Interferons and natural killer (NK) cells
    • Interferons are proteins made and secreted by cell in response to viral infection
      • induced by dsRNA from these viruses and in the replication process of ssRNA
      • protect adjacent cells from infection
      • activates T-cell mediated immunity
  • 6. Interferon
    • Most cells make both  and  that diffuse to nearby cells to trigger various antiviral activities by binding receptors
      • activation of genes that encode antiviral proteins – dsRNA dependent protein kinase R and Rnase L
      • stimulate MHC I molecules and proteosome proteins – enhance presentation of viral peptides on surface of cell to T-cells
      • activate NK cells
      • induction of apoptosis
  • 7.  Interferon
    • Made mainly by T-cells and NK cells triggered by certain molecules such as interleukin-2 during the immune response
      • stimulates antigen presentation
      • activation of phagocytes and NK cells
  • 8. Viral Countermeasures
    • Viruses try to prevent the production of the these proteins or try to interfere with their activities
      • NS1 of influenza and NS3-4A of hepatitis C block pathway of production
      • poliovirus prevents synthesis of interferon as result of general inhibition of cellular gene expression
  • 9. Natural Killer (NK) Cells
    • Throughout the body but mostly in the blood
    • Recognize changes in surface molecules of virus-infected cells but not the specific antigens like B- and T-cells
    • NK cells bind to infected cell and then kills them and can also release interferon 
    • 2 mechanisms
      • release perforins – proteins that when inserted into plasma membrane make pores and cell dies
      • induce apoptosis
  • 10. Viral Countermeasures
    • HIV particles in the blood alters the expression of a number of molecules on surface of NK cells, reducing effectiveness in killing viral-infected cells and to make/secrete  interferon
  • 11. APOBEC 3 Protiens
    • Enzymes in cells – humans and animals – that interfere with retrovirus replication
      • make lethal mutations by deaminating deoxyctidine to deoxyuridine during reverse transcriptase
    • Several of these proteins in human cells can interfere with replication of HIV – APOBEC 3F and 3G – incorporated into HIV virion
      • wreaks havoc in the next cell infected
  • 12. Viral Countermeasures
    • HIV infected cell has Vif protein that binds APOBEC 3G and causes its degradation
      • cannot be incorporated into HIV particle
  • 13. Adaptive Immunity in Vertebrates
    • Outcome of virus infections in vertebrate host is development of virus – specific immune response
    • Regions of antigens known as epitopes, bind to specific receptors on lymphocytes and activating a cascade of events that result in an immune response
    • 2 classes of lymphocytes – each is specific for a particular epitope as a result of presence of epitope-specific receptor on cell surface
      • B-cells – develop in the Bursa of Fabricuis in birds and bone marrow in mammals
      • T-cells – develop in the thymus
    • Naïve lymphocytes – have not encountered their epitope – keep circulating and have different surface molecules
      • distinctly different than cells exposed to epitope
  • 14. Antibodies
    • Glycoprotein known as immunoglobulins (Ig)
    • Basic structure looks like a Y and is made of 2 heavy chains and 2 light chains with 2 binding sites for antigen (F ab ) and a region known as the F C for fragment crystallizable
    • Several classes of Ig – most imortant in view of antiviral immunity being IgG and IgM in the blood and IgA in mucosal surfaces
      • IgG is a monomer and IgA and IgM are dimers and pentamers respectively
  • 15. Plasma Cell
    • Ag specific Ab are made by plasma cells – made from B-cells after it has been stimulated by interaction between Ag and specific receptor at the cell surface
  • 16. Role of Antibodies
    • Play important roles in several aspects of anti-viral immunity based on its structure – Ab binds to Ag and then the cell or virus is destroyed by various mechanisms
      • neutrophils and macrophages will phagocytize Ab-coated cells and viruses because have an F C -receptor on surface, may kill without phagocytosis
      • NK cells may be activated to kill cell with perforins
      • activation of the complement system which has a number of antiviral effects
        • insert complement proteins complexes into membrane a virus infected cell or enveloped virus – kills them
        • complemented coated virions can trigger phagocytosis by neutrophils and macrophages – have receptors for complement proteins
  • 17. Additional Ab Effects
    • Ab binds to virion and can neutralize infectivity by a variety of mechanisms
      • release of nucleic acid from virions – poliovirus = Ab attaches and when detaches, the capsid is empty of genome
      • prevent attachment to cell receptors – Ab masks virus attachment sites, not all sites are accessible to Ab – picornovirus in deep canyons
      • release of virions that have attached to cell receptors
      • inhibition of entry into cell – Ab coating fusion proteins on enveloped virion may inhibit fusion with cell membrane
      • inhibition of genome uncoating
  • 18. T-Cells
    • After Ag stimulation naïve or memory T-cells develop into effector T-cells – 2 classes
      • helper T-cells – secrete specific cytokines and characterized CD4 on surface – essential roles in initiation of immune response
        • help trigger B-cells in Ab secreting cells and maturation of cytotoxic T-cells
      • cytotoxic T-cells – kill virus infected cells, characterized by CD8 on surface – viral Ag must be expressed on surface of target cell
        • surface proteins like envelope glycoproteins but most often internal virion proteins or non-structural proteins
        • CTL can remove early infection cells before more virus made
    • Ag displayed on infected cells on MHC I on surface and trigger CTL action – insert perforin into membrane or induce apoptosis
  • 19.  
  • 20. Viral Countermeasures
    • Some viruses like HSV reduce level expression of MHC I – makes more difficult for CTLs to recognize infected cells
  • 21. Immunological Memory
    • Quantity and quality of adaptive immune response depends on whether virus is encountered for the first time
    • B and T cells can serve as memory cells long after first or subsequent encounters
      • memory – return to resting state to be reactivated when exposed to Ag again
      • can be from natural Ag or from Ag in a vaccination
    • If host has memory – signs and symptoms may be less severe or absent on subsequent exposures
  • 22. RNA Silencing
    • Also known as post-transcriptional gene silencing or RNA interference (RNAi)
    • Intracellular processes induced by dsRNA – causes destruction of mRNA that have the same sequence as the inducing dsRNA
      • both cellular and viral mRNAs can be destroyed
  • 23. RNAi Mechanism
    • Cleave dsRNA into small interfering dsRNA (siRNA) 21-25 bp using a complex with Dicer (Rnase III family)
      • leaves a 3’ overhang of 2-3 nt
    • siRNA binds to complex to make RISC (RNA induced silencing complex)
    • siRNA is unwound and (-) strand stays with RISC causing on active complex
    • (-) strand finds complementary mRNA, mRNA degraded where double-stranded
    • Found in plants, fungi, invertebrates, vertebrates (animals)
      • important anti-viral defense mechanism, may be for rest also
    • Induced when add synthetic dsRNA to cell
  • 24.  
  • 25. Viral Countermeasure
    • Some plants make proteins to inhibit silencing
      • helper-component proteinase of potyvirus and P19 protein of tombusvirus – both strong suppressors
  • 26. Programmed Cell Death
    • Kill the cell before can release new viruses – called apoptosis
    • Also functions when cell reaches end of life span
    • Bacteria has mechanism to cause cell death as well – again prevents spread to other bacteria
  • 27. Viral Countermeasure
    • Viruses can make proteins that can control the process of apoptosis
      • some DNA viruses make a protein similar to BCL-2 that controls apoptosis = block the process
  • 28. Non-Productive Infection
    • Replication cycle is not completed – 2 outcomes
      • latent infection – genome persists but no virus
      • abortive infection – any other thing
  • 29. Latent Infection
    • Initiated when virus genome is maintained is maintained in the infected cell – integrate into cell DNA or maintained copies of covalently closed circular DNA (episomes)
    • Eukaryotic cells – viral DNA associated host cell histones – help with latency
  • 30. Retrovirus Latency
    • Retroviruses – early in infection integrate into host genomes, infection doesn’t progress, if intracellular environment changes to favorable the latent infection can become a productive infection
  • 31. Bacteriophage Latency
    • Phenomenon of latent phage infection in bacterium = lysogeny
      • phage is said to be temperate
      • prophage (genome of the phage) persists in cell – can integrate into genome or as non-integrated circular DNA
      • temperate phage genomes – may encode gene to have selective advantage on host – sometimes have virulence factors like Shiga toxin in E coli
  • 32. During Latency
    • Genome may be shut down or may have a few genes expressed – proteins or non-coding RNA
      • if cell divides, nee daughter cell gets viral genome too – replicate without hurting cell
    • Latent cells can become productive infection = induction can occur if following happen
      • eukaryotic host cell moves into another phase of cell cycle
      • exposure to UV light – phage to lyse bacteria or HSV to cause cold sore
      • immunocompromised host – HSV
      • host infected with 2 nd virus (helper virus) – provide function lacking in 1 st virus (satellite virus)
  • 33. Examples of satellite/helper viruses Satellite virus Helper virus Hepatitis delta virus Hepatitis B virus Adeno-associated viruses Adenovirus
  • 34. Abortive Infection
    • Non-productive and genome doesn’t persist
    • May be abortive because of cell, environmental conditions and/or virus
    • May be productive in permissive cells but abortive in non-permissive cells
    • Infection may kill cell before make more virus
    • Virus may be mutant – good enough to start infection but not to finish – virus is said to be defective
  • 35. Types of Defective Viruses
    • Number of different types
    • Defective interfering particle (DIP) – happens in lab after animal virus passed several times in cell culture at high MOI
      • see also in chick embryos, in mice and in plant viruses
      • DIPs have less genome than normal – are either non-infectious or can do only abortive infections
      • if cell infected with normal virus and DIP – DIP can replicate but “interferes” with replication of normal viruses
  • 36. Productive Infections
    • Spread of infections within multicellular hosts
      • virus may spread to nearby cells – common cold virus and rotavirus may infect additional respiratory and gastrointestinal epithelial cells – direct cell to cell spread
    • Plant viruses move thru plasmodesmata – virus encodes 1 to 4 proteins to enable this = movement proteins (MP) – different functions
      • complex with viral RNA
      • or with RNA + coat protein
      • form tubular structures thru which encapsidated RNA is transported, also roles in viral replication
    • May move distances in host – blood and nerves in animals and phloem in plants
  • 37. Disease
    • Many viral infections result in no disease to host while others are fatal (rabies and HIV)
    • Many manifest as symptoms (subjective like pain; recognized by patient only) or signs (objective like skin rash, blood in stool; recognized by others)
    • Infections that do not cause disease are said to be subclinical or asymptomatic
    • Outcome is based on complex interplay with virus factors, host factors and human intervention
    • Not all viruses are pathogenic and some only pathogenic under certain conditions
  • 38. Pathogenic Virus Factors
    • 1 – virulence of strain – measure of severity of disease it causes
      • influenza A H5N1 more virulent than H1N1 and H3N2 - H5N1 is more severe cause of disease
    • 2 – dose of virus – large dose can shorten incubation period – time between infection and 1 st signs/symptoms
  • 39. Host Factors
    • Immune system effectiveness based on age and nutritional status of host
      • strong immune may not mean complete elimination of virus
        • HIV still replicates in high Ab titer and T-cells
      • symptoms/signs may be response of immune system
        • measle rash and HSV lesion – clinical manifestation of attempts to destroy virus-infected cell
  • 40. Human Intervention
    • Anti-viral Ab or anti-viral drugs
    • Recovery – may clear virus completely or may establish long-term infection
      • may be persistant or latent
      • no further problem or cause problems later, may lead to cancer as well
        • Varicella-zoster – chicken pox as kid; shingles as adult
  • 41.  
  • 42.