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Flashcards

Dr Lowe, Lec 2, Host Evasions

Emma Lloyd Microbes and Man English 43 cards

Cards in this deck (43)

  1. 1What is immunoglobulin M?IgM is an antibody. They are the largest of the antibodies and respond to initial antigen exposure (not repeated exposures). IgM is broad and not highly specific, yet can aid in killing viruses
  2. 2What is the germinal receptor response?B cells that encounter a viral antigen need to have their B cell receptor stimulated to develop this response. It is where they undergo somantic hypermutation and their IgM genes mutate in a way that massively increases specificity to the target virus
  3. 3What is class switch recombination?Response goes from IgM to IgG which is highly specific to the target virus
  4. 4What is influenza?It is a virus with 8 individual RNA fragments that all encode different proteins. The M2 protein forms a more so when the virus is endocytosed it allows molecules in to break down the viral capsid
  5. 5What are the two major influenza proteins?Hemagglutanin (HA) - a virus protein that is essential for the virus to enter the cells that works by interacting with sialic acid on the membrane of the host
    Neuroaminidase (NA) - enzymes that cleave the glycosidic linkages of neuraminic acids
  6. 6How can we stop the entry of the virus?With neutralising antibodies that inhibit the interaction between hemogglutanin and sialic acid
  7. 7How do antibodies protect against infection?- bind to viruses
    - prevent viruses from reaching host cell
    - neutralise the virus binding to receptor
    - activate/fix the complement
    - antibody dependant cell mediated cytotoxicity (ADCC)
    -activate phagocytosis (opsonization)
    - interfere with virus propagation
  8. 8How does influenza evade mediated neutralisation of infection?By antigenic variation via antigenic shift/antigenic drift. It allows influenza to infect the host repeatedly, whilst other viruses usually have immunity built against them after the first infection
  9. 9What is antigenic variation?The change of viron proteins in response to antibody selection
  10. 10What is antigenic drift?Amino acid variation in structurally plastic proteins (quite common)
  11. 11What is antigenic shift?A major change in the surface protein of a viron as a result of recombination between two co-infecting viral serotypes (rare and distinct) and results in a whole new virus which often causes bandemics, eg, bird flu
  12. 12Example of antigenic shift?A virus usually has neutralising antibodies blocking its haemagglutanin form binging to host sialic acid. Mutation by antigenic shift could cause antibodies to no longer block this interaction.
    The antigenic drift alternative would just be a mutation of the specific antibody blocking the receptor
  13. 13Process of original antigenic sin?1. Individual, aged 2, infected w/ influenza. Makes antibodies against all present epitopes on this virus strain
    2. Individual, age 5, infected with influenza variant. Only makes antibodies against epitopes that are in this strain that were also in the first strain
    3. Age 20, individual meets new variant of influenza. Can only protect against epitopes from first 5 years of life
  14. 14What is an epitope?The part of the antigen molecule to which the antibody attaches itself
  15. 15Why do mutations like antigenic drift/shift happen?RNA viruses like influenza replicate their genomes using RNA polymerase that lacks the proof-reading ability of DNA polymerase. RNA viruses have much higher mutation rate than DNA viruses. RNA viruses can also alter antigenic epitopes targeted by the immune system
  16. 16Difference between drift and shiftIn antigenic drift, the antibodies are no longer attached to the epitope stopping binding (due to mutation). In shift, the exchange of RNA segments between dif viral strains occurs in secondary host and there is no cross protective immunity
  17. 17Pandemics caused by antigenic shift:-1918 Spanish influenza (H1N1)
    -1957 Asian influenza (Mix of H1N1 and H2N2)
    -1968 Hong Kong influenza which was a mix of Asian influenza and H3 viruses
    It is likely antigenic shift will cause another similar inflenza pandemic
  18. 18Where does the mixing of two different influenza viruses happen?No in humans but in other animals like pigs and birds. Bird and pig influenzas bind to different sialic acids. Pigs have sialic acids for both bird and human influenza viruses to bind to, however, so they make a very good mixing pot for influenza strains
  19. 19How did bird flu come about?The mixing of the gene segments from influenza in ducks, domestic poultry and wild birds making a H7N9 virus
  20. 20Summary of antigenic drift- only minor antigenic change
    -only one virus involved
    -occurs frequently
    -infects same species of animal
    -small mutation of RNA
    -random + spontaneous
    - occurs in influenza A, B and C
    -accumulation of point mutations
  21. 21Summary of antigenic shift- major antigenic changes
    -two or more viruses involved
    -occurs rarely
    -can jump from species to species
    -large RNA nucleotide changes
    -large and sudden
    -only in influenza A's
    -genome reassortment between dif subtypes
  22. 22What is antigenic variation dependent upon?It depends on the structural plasticity of the structural proteins. The more structurally plastic a virus is, the less antigenic variation it experiences
  23. 23What does antigenic variation have a considerable impact on?The success of vaccination strategies
  24. 24Why are these antigenic variation epitopes so common?Replicating RNA viruses average a mistake every 10^4-10^5 nucleotides. These mutated RNA viruses then go onto produce progeny and viruses produce a large volume or progeny at a time, eg, in vito a single poliovirus cell can produce 10^5 progeny. This spreads mutated strain.
  25. 25Summary of lifecycle of ebola:1. Attaches to receptors on host cell surfaces such as TIM-1, Axl, DC-SIGN, c-type lectins, integrins, etc
    2. Triggers cell to marcopinocytose the virus (engulf through cell membrane ruffles)
    3. virus furses with macorpinosome and binds to NPC1
  26. 26Ebola life cycle cont.4. NPC1 is a protein that releases the virus into the cytoplasm
    5. Virus produced and released from the cell via budding. Antibody response is usually seen here and the pro-inflammatory response is triggered
  27. 27How does ebola enter the body?It is too large to enter cells by endocytosis so requires endopinocytosis. It has a mechanism known as apoptotic mimicry. The primary cells for ebola to enter are macrophages, monocytes and dendritic cells. This should activate the immune response.
  28. 28Apoptosis triggers phospholipid flipping in membranes. What does this entail?Usually, the part of the bilayer facing the cell cytoplasm contains phosphotidylseine but when apoptosis is triggered, the phosphotidylseine is flipped into the outer membrane too. This triggers macropinocytosis if it happens in phagocytic cells. It is mediated by TIM-2 and Axl. Doesn't induce inflammation.
  29. 29How did ebola encapsulate this to do molecular mimicry?Ebola was covered in phosphotidylserine which triggered it to be macropinocytoed like when apoptosis is triggered in regular cells
  30. 30What RNA sensing would ebola usually trigger?Should trigger innate immune system as its RNA would trigger RIG-1 receptor pathway. RIG-1 recognises ss/dsRNA that has been 5' triphosphoryated. Mda5 is protein that recognises long strands of ssRNA and TLR-3 recognises dsRNA. If either of these are triggered, they itneract with mitochondrial
  31. 31previous card cont.protein MAVs. MAVs cause downstream signalling to interferon to produce pro-inflammatory immune response.
    Influenza has to get around this system
  32. 32What is responsible for avoiding this mechanism?VP35 prevents induction of type 1 interferon so stops pro-inflammatory cytokine production. It interacts with N-terminal kinase domain of IKKe and prevents IRF3 phosphorylation (a downstream molecule).
  33. 33What can VP35 do?Contains c-terminal inferferon inhibitory domain (IDD) which is made of 2 clusters of basic amino acids. It binds to blunt ends of dsRNA to prevent RIG-1 binding and Mda5
  34. 34Which T cells are usually activated to act against ebola?CD8 T cells but requires multiple signals
  35. 35Signal 1: Activation summaryT cells naive towards virus before encounter. In order to become activated and differentiate into functional cytotoxic T cells, they must have certain signals from dendritic cells. Dendritic cells must display foreign antigen as MHC-1 complex to activate the T cell
  36. 36Signal 2: Survival summaryDendritic cells express CD80 and CD86. When this interacts with CD28, on naive cells, it simulates the survival signal
  37. 37Signal 3: Differentiation summaryDifferentiation is triggered by signals from dendritic cells derrived from cytokines. T cells can then become multiple types of functional T cells
  38. 38How can T cells become able to kill ebolaNaive T cells becomes effector T cells complimentary to receptors on ebolavirus infected cells. Can now kill them.
  39. 39How does ebola evade all of this?Inhibits the pro0inflammatory cytokines required for the T cell differentiation
  40. 40What does antibody decay mean in regards to ebola?In recent ebola outbreak, some people died rapidly but some survived. Scientists theorise that this may be due to the viral dose. If viral dose is big there is no time to produce antibody. Also, if there is a poor IgG response the infection is likely to be fatal but if patient has a high IgG response they're likely to survive
  41. 41Structure of ebola?Large, fillamentous and high density glycoprotein virus. Folding can create glycoprotein pockets which may resist access of vital neutralising epitopes so it can't access the area needed to neutralise it. Key receptor binding domains can alsi be hidden behind glycan caps
  42. 42How does ebola avoid neutralising antibodies?Once virus has been manufacutred, it moves to the cell membrane where it gains glycoproteins as it leaves. These attract neutralising antibodies. To avoid this, ebola releases soluble glycoproteins from the cell first to 'mop up' the neutralising antibodies
  43. 43What can ebola cause physiccally?Can cause heomorrhage by glocoproteins interacting with the phagocytic cells, stimulating TLRs which downstream make proinflammatory cytokines. In endothelial cells, cytokines loosen tight junctions allowing molecules to move in and out of cells (like blood, leading to heomorrage)

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Microbes and Man Flashcards on Dr Lowe, Lec 2, Host Evasions , created by Emma Lloyd on 07/05/2019.
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Emma Lloyd
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