Chapter 9 Outcomes of Infection for the Host
Productive Infection <ul><li>Infected cell releases some new viruses  </li></ul><ul><li>Host cell may lyse or may survive ...
Persistance <ul><li>Virus may persist for long times in the host and are productive like HIV-1 or may persist with periods...
Effect of Virus on Host <ul><li>Effect on host can range from harmless to deleterious (death) </li></ul><ul><ul><li>outcom...
Innate Immunity in Vertebrates <ul><li>Interferons and natural killer (NK) cells </li></ul><ul><li>Interferons are protein...
Interferon <ul><li>Most cells make both    and    that diffuse to nearby cells to trigger various antiviral activities b...
   Interferon <ul><li>Made mainly by T-cells and NK cells triggered by certain molecules such as interleukin-2 during the...
Viral Countermeasures <ul><li>Viruses try to prevent the production of the these proteins or try to interfere with their a...
Natural Killer (NK) Cells <ul><li>Throughout the body but mostly in the blood </li></ul><ul><li>Recognize changes in surfa...
Viral Countermeasures <ul><li>HIV particles in the blood alters the expression of a number of molecules on surface of NK c...
APOBEC 3 Protiens <ul><li>Enzymes in cells – humans and animals – that interfere with retrovirus replication </li></ul><ul...
Viral Countermeasures <ul><li>HIV infected cell has Vif protein that binds APOBEC 3G and causes its degradation </li></ul>...
Adaptive Immunity in Vertebrates <ul><li>Outcome of virus infections in vertebrate host is development of virus – specific...
Antibodies <ul><li>Glycoprotein known as immunoglobulins (Ig) </li></ul><ul><li>Basic structure looks like a Y and is made...
Plasma Cell <ul><li>Ag specific Ab are made by plasma cells – made from B-cells after it has been stimulated by interactio...
Role of Antibodies <ul><li>Play important roles in several aspects of anti-viral immunity based on its structure – Ab bind...
Additional Ab Effects <ul><li>Ab binds to virion and can neutralize infectivity by a variety of mechanisms </li></ul><ul><...
T-Cells <ul><li>After Ag stimulation naïve or memory T-cells develop into effector T-cells – 2 classes </li></ul><ul><ul><...
 
Viral Countermeasures <ul><li>Some viruses like HSV reduce level expression of MHC I – makes more difficult for CTLs to re...
Immunological Memory <ul><li>Quantity and quality of adaptive immune response depends on whether virus is encountered for ...
RNA Silencing <ul><li>Also known as post-transcriptional gene silencing or RNA interference (RNAi) </li></ul><ul><li>Intra...
RNAi Mechanism <ul><li>Cleave dsRNA into small interfering dsRNA (siRNA) 21-25 bp using a complex with Dicer (Rnase III fa...
 
Viral Countermeasure <ul><li>Some plants make proteins to inhibit silencing </li></ul><ul><ul><li>helper-component protein...
Programmed Cell Death <ul><li>Kill the cell before can release new viruses – called apoptosis </li></ul><ul><li>Also funct...
Viral Countermeasure <ul><li>Viruses can make proteins that can control the process of apoptosis  </li></ul><ul><ul><li>so...
Non-Productive Infection <ul><li>Replication cycle is not completed – 2 outcomes </li></ul><ul><ul><li>latent infection – ...
Latent Infection <ul><li>Initiated when virus genome is maintained is maintained in the infected cell – integrate into cel...
Retrovirus Latency <ul><li>Retroviruses – early in infection integrate into host genomes, infection doesn’t progress, if i...
Bacteriophage Latency <ul><li>Phenomenon of latent phage infection in bacterium = lysogeny  </li></ul><ul><ul><li>phage is...
During Latency <ul><li>Genome may be shut down or may have a few genes expressed – proteins or non-coding RNA </li></ul><u...
Examples of satellite/helper viruses Satellite virus Helper virus Hepatitis delta virus Hepatitis B virus Adeno-associated...
Abortive Infection <ul><li>Non-productive and genome doesn’t persist </li></ul><ul><li>May be abortive because of cell, en...
Types of Defective Viruses <ul><li>Number of different types </li></ul><ul><li>Defective interfering particle (DIP) – happ...
Productive Infections <ul><li>Spread of infections within multicellular hosts </li></ul><ul><ul><li>virus may spread to ne...
Disease <ul><li>Many viral infections result in no disease to host while others are fatal (rabies and HIV) </li></ul><ul><...
Pathogenic Virus Factors <ul><li>1 – virulence of strain – measure of severity of disease it causes </li></ul><ul><ul><li>...
Host Factors <ul><li>Immune system effectiveness based on age and nutritional status of host </li></ul><ul><ul><li>strong ...
Human Intervention <ul><li>Anti-viral Ab or anti-viral drugs </li></ul><ul><li>Recovery – may clear virus completely or ma...
 
 
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Chapter 9

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Chapter 9

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