IMI 7: Immune Responses to Intracellular Pathogens Flashcards

1
Q

Observe the learning outcomes of this session

A
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2
Q

What are intracellular microbes able to do that obligate extracellular pathogens cannot?

A
  • intracellular microbes have evolved to take advantage of the environment inside cells
  • obligate extracellular pathogens lack strategies to enter and/or survive in human cells
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3
Q

Describe the two main classes of intracellular microbes

A
  1. Obligate intracellular pathogens cannot reproduce outside the host cell.
    - Typically, they require the cells’ metabolic energy and biosynthetic processes for their proliferation.
    - For instance, all known viruses require the host cell’s ribosomes to translate their mRNAs.
    - Since they still need to leave the cell to spread, they typically have a distinct - often inactive - extracellular form to survive in the outside environment, such as virus particles, bacterial spores, or encapsulated cells.
  2. Facultative intracellular pathogens can survive and proliferate in the extracellular environment, but they can also invade host cells.
    - For instance, this might allow the bacterium or parasite to cross a cell (e.g. by traversing gut cells to enter the body) or to survive in the phagosomes.
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4
Q

Are intracellular pathogens equipped to survive the extracellular environment?

A
  • Remember that intracellular pathogens do still need strategies to survive the extracellular environment that they must face when they spread within and transmit between their hosts.
  • They are typically equipped to gain access to human tissues without the need for a scratch or abrasion, and have specific mechanisms to enter cells.
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5
Q

What are the two phases required for dealing with an intracellular pathogen?

A
  1. Detecting that a pathogen is there
  2. Destroying, inactivating or incapacitating the pathogen once it has been found
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6
Q

What are the three elements that almost all virus particles (virions) have?

A
  1. A genome, made of DNA or RNA (or sometimes a bit of both)
  2. A protein that packages the genome, either like beads on a string (nucleoprotein), or in a protein shell (capsid).
  3. A protein on the virion surface that binds specifically to a cell surface molecule, allowing the virus to enter the cell.

Therefore, these are universal features (potential PAMPs) that our immune system tries to spot, but equally are features that the virus can adapt to avoid immune detection and elimination

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7
Q

What are the three main characteristics that vary between viruses?

How does this reflect in the immune response?

A
  1. What nucleic acid their genome is made of: DNA or RNA; single or double stranded
  2. Whether or not they have a lipid envelope surrounding their packaged genome.
  3. Whether they replicate their genome in the cytoplasm or the nucleus

The variation between viruses is defines what immune response will be effectibe at sensing and/or targeting the virus

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8
Q

Observe how viruses can vary according to the three charactersitics that vary

A
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9
Q

Describe the virus lifecycle in a cell in general

A
  1. Entry
  2. Genome transport
  3. Transcription and translation of gene products
  4. Genome replication
  5. Packaging
  6. Exit

image is an example of a herpes virus

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10
Q

What are the differences between how different viruses manage their life cycle?

How does this affect what the immune system might do to detect and act against them?

A
  • Entry might be fusion at the cell membrane (where an enveloped virus will leave remnants of its membrane on the surface), or by endocytosis where the virus might hide in a vesicle while it travels about the cell.
  • The genome may be transported to the nucleus, or may move to a (often membrane-rich) region of the cytoplasm for its replication.
  • A virus might execute a short lived and rapidly cleared (acute infection) but highly productive reproduction process, or might invade and set out for a long stay (persistent/chronic infection), quietly manipulating its host cell, or even shutting down all its protein production (latent infection) until it can re-emerge at a later time or different place.
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11
Q

Why do some viruses cause immense damage to the host, while others we barely notice?

A

The pathogens that are successful at infecting our bodies are the ones that have evolved to disable or avoid (the technical term is ‘evade’) our immune system’s defences.

  • The constant arms race between pathogen and immune system means that many pathogens have evolved to be effective at surviving and spreading in relatively small group of host species.
  • This is why in the example in IMI5, it took the generation of an adaptive immune response to rid our body if the influenza virus.
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12
Q

What are the most broadly important PRRs for identifying virus infection?

What are the challenges faced by the immune system?

A
  • those that recognise viral genomes
  • the challenge is to distinguish between the nucleic acids making up virus genomes from the DNA or RNA molecules that are part of normal cell biology that do us no harm
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13
Q

When is it easiest to recognise nucleic acids?

Give an example

A
  • when they are in a location that they should no be
  • e.g. in a healthy interphase cell, DNA should be retained within the nucleus and mitochondria
  • therefore, any sensing DNA in the cytoplasm should ring cellular alarm bells that something has gone wrong
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14
Q

Give an example of a key sensor of cytoplasmic DNA

Explain how it works

A
  • cyclic GMP/AMP synthase (cGAS)
    1. cGAS binds to DNA in the cytoplasm
    2. cGAS generates cGAMP
  • once activated by DNA binding, cGAS, catalyses the formation of a small cyclic dinucleotide made from ATP and GTP that can freely diffuse in the cell as a second messenger
    3. Bacterial cyclic dinucleotides
  • as part of their natural processes, many bacteria produce cyclic dinucleotides that are not normally produced in eukaryotic cells
  • these can be sensed as PAMPs, indicating a bacterial infection of the cell
    4. Cyclic dinucleotides bind to STING
  • cyclic dinucleotides can diffuse through the cytosol and bind to STING (stimulator of interferon genes) and activate its functions by recruiting the protein kinase TBK1 (also involved in TLR signalling)
    5. TBK1 phosphorylates IRF3
  • TBK1 phosphorylates IRF3, which then migrates into the nucleus
    6. NKfB activation
  • TBK1 phosphorylates IKK, which then liberates NFkB, allowing it to migrate into the nucleus
    7. Gene activation:
  • IRF3 and NFkB migrate to the nucleus and bind to the promoters of immune genes, resulting in the transcription of (most importantly) type I interferons and also various cytokines
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15
Q

Apart from virus infection, what is the cGAS/STING pathway also important in?

A
  • Since the discovery of the cGAS/STING pathway in the context of virus infection, this mechanism of DNA sensing has been shown to be important in other processes that relate to the cell’s health, such as mitochondrial integrity, DNA damage and errors in cell division.
  • As a result, the function of cGAS and STING in cancer biology is a highly active and exciting area of research right now.
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16
Q

Give an example of another group of DNA sensors that is not cGAS

A
  • AIM2-like receptors (ALRs)
  • this family of related DNA-binding proteins contains pyrin domains
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17
Q

What biological process is mediated by pyrin domains?

A
  • pyrin domains facilitate the formation of inflammasomes
  • And just like the NLRs (IMI4), the ALRs AIM2 and IFI16 can form multimers (in this case dependent on binding long DNA molecules) that recruit caspases to assemble an inflammasome that activates pro-inflammatory cytokines like IL-1β.
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18
Q

Why is sensing viral DNA in the nucleus trickier?

A
  • in an environment full of DNA, how can the cell tell viral from cellular DNA?
  • This remains an open research question.
  • There are known protein complexes that can suppress the transcription of viral DNA in the nucleus, but how these systems identify viral DNA as foreign remains unresolved.
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19
Q

How is endosomal DNA sensed?

A
  • endosomes represent that twilight zone that is neither the external nor intracellular environment: they are like a bubble of the external environment held within the cell.
  • Cytosolic sensors do not penetrate this space, so we are reliant on the endosomal TLRs (3, 7, 8 & 9) for sensing in endosomes, described in IMI1.
  • In IMI1, you encountered TLR9, which detects DNA whose CpG dinucleotides are unmethylated.
  • Since the vast majority of CpG dinucleotides in genomic DNA are methylated, this is particularly important for APCs to sense bacterial or viral genomes that have been released after degradation of phagocytosed pathogens.
  • Similarly, TLR3 is important for sensing RNA released from degraded cells, or viruses with RNA genomes.
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20
Q

How is foreign RNA sensed?

A
  • in contrast to DNA, it is very common to find RNA in the cytoplasm and nucleus
  • e.g. mRNA in the cytoplasm and pre-mRNA in the nucleus
  • therefore, intracellular PRRs that sense viral RNAs cannot rely on RNA location
  • instead they recognise features of viral RNAs that are not shared by cellular RNAs
  • so, we consider the biology of RNA viruses
  • they rely on their RNA-dependent RNA polymerase to transcribe RNA from RNA, which is unnatural to a eukaryotic cell
  • therefore, RNA sensors recognise features that are specific to this process, but not other present in our cells
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21
Q

Give examples of RNA sensors and what in foreign RNA do they sense?

A
  1. Detecting uncapped RNA: by RIG-I, which senses shortish RNAs
  2. Sensing double stranded RNA:
    e. g. MDA5: senses long (>2000 nucleotide) double stranded RNA (dsRNA)
    - This dsRNA is an unavoidable consequence of synthesising RNA on an RNA template, so it will always be produced during RNA virus replication or transcription.
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22
Q

Describe the signalling cascade triggered when RIG-I-like receptors (RLR) bind to RNA?

A

Both RIG-I and MDA5 are members of the RIG-I-like receptor (RLR) family, that was briefly introduced in IMI1. When RLRs bind to RNA, they activate a signalling cascade by causing the multimerisation of the mitochondrial protein MAVS:

  1. RIG-I assembly on foreign RNA:
    - RIG-I binds and assembles on foreign RNA
    - and they can slide along, allow the multimerisation of its CARD domain
  2. Activation of MAVS signalling complex:
    - the CARD domains of RIG-I bind to the CARD domains of MAVs
    - resulting in a clustering of the MAVs protein on the mitochondrial membrane
    - this clustering activates MAVs
  3. Activation of transcription factors:
    - like other sensors, MAVS uses TBK1 and TRAFs to induce phosphorylation events that activate transcription factors:
    - Interferon Regulator Factor 3 and 7 (IRF 3/7)
    - NFkB
  4. Activation of interferon and inflammatory genes
    - these transcription factors then activate immune genes, particularly type I interferons (by IRFs) and pro-inflammatory genes (by NFkB)
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23
Q

How do viruses evade nucleotide sensing?

A
  • In order to successfully infect and thrive in us, viruses have evolved gene products that evade genome sensing by the cell.
  • This will typically take the form of binding and inhibiting, or ubiquitinating and degrading components of these innate immune responses.
  • Examples include:
  • blocking RNA sensing pathways
  • cap snatching
  • inhibition of DNA sensors
  • do not need to memorise these but the explanations are in the e-module
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24
Q

What are the three classes of IFNs?

A
  • Type I IFNs (including all twelve IFN-α subtypes and IFN-β) are produced in response to pathogen-induced signals in the infected cells
  • It signals to nearby cells of all types (as we will see shortly).
  • Type II IFN (which includes just IFN-γ) is produced by activated immune cells.
  • It mainly signals to modulate the responses of other immune cells.
  • Type III IFNs (three IFN-λ subtypes) are structurally related to IL-10 but – like type I IFNs – lead to an antiviral state in cells infected with a virus.
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25
Q

What are the two key roles of IFNs?

A
  • Firstly, like many cytokines, the IFNs can activate and attract cells of the immune system.
  • Secondly, non-immune cells can also respond to IFNs.
  • In response to IFN signalling, nearby cell turns on a whole suite of IFN-stimulated genes (ISGs).
  • This places the cell in a state of alert – an antiviral state – in order to better prevent or limit viral infection and replication.
26
Q

Which, out of the two key roles of IFNs, is its most distinctive characteristic?

For which type of IFNs in particular?

What are the implications of this?

A
  • the ability to manipulate non-immune cells is its most distinctive characteristic
  • specifically in type I and III IFNs
  • this is what makes them different from other cytokines
  • key implications:
  • The production of IFNs is not to save the infected cell: viruses are fast (and, in any case, IRFs induced by PRRs induce ISGs as well as IFN).
  • Rather, the secreted IFN molecules will warn the nearby cells to gear up their defences.
  • This is both in terms of activating immune cells, and preparing non-immune cells to block their infection.
  • This makes it harder for the pathogen to infect new cells, and spread.
27
Q

What triggers the antiviral state?

A
  • The binding of IFN to its receptor leads to a signalling cascade that triggers the transcription of a large number of ISGs – genes that code for proteins that help fight viruses.
  • Signaling in response to IFNs thus triggers an antiviral state.
28
Q

Can all IFNs induce an antiviral state?

How does it differ in vitro and in the human bodies?

A
  • Note that all types of IFNs (type I, II and III) can induce an antiviral state (at least in vitro in a cell culture set-up like the one you use in the Lab Pods).
  • In our bodies, however, type II IFN (IFN-γ) works more like a modulator of immune responses, while type I and type III IFNs lead to the antiviral state.
29
Q

Give some examples of interferon-stimulated genes

A
  • antiviral PRRs
  • components of the immunoproteosome
  • activatory receptors
  • restriction factors
30
Q

What are restriction factors?

A
  • Restriction factors are cellular gene products that can prevent specific pathogen functions.
  • Typically they have both a sensing (specificity) and an effector component, being able to both detect and ‘destroy’ (or at least inhibit) a specific pathogen.
  • For instance, they might bind a capsid so it is degraded, or tie it to a cellular structure so it can’t escape.
  • However, they often have quite a narrow range of pathogens they can target.
  • As a result, there are many restriction factor genes in our genome to ensure that our cells are be able to handle the wide variety of pathogens that try to take advantage of us.
  • The fact that there are so many may also be why we need IFN - we only spend the extensive resources for making all these proteins when we know we might really need them.
31
Q

Which of the following cells benefit from the release of interferon by virus-infected cells?

A
  • nearby infected cells
  • antigen-presenting cells

The effects of interferon are mainly local, and they perform both regular cytokine-like functions (activating immune cells associated with combating intracellular infection) and induce the antiviral state, which increases a cell’s innate defence against infection.

Cells that are infected are already doomed, so will not benefit from the release of interferons: the virus will kill them before the infected cell has time to transcribe and translate the ISGs.

32
Q

Match the PRR to the associated PAMP

A
33
Q

Which of the following lead to Interferon production?

A
  • RNA detection in endosomes by TLR3
  • sensing DNA in the cytoplasm
  • sensing uncapped RNAs in the cytoplasm

As you have learned in IMI4, the inflammasome is an entity that specifically catalyses the cleavage and activation of pro-inflammatory cytokines, so does not directly lead to IFN production. All these other stimuli do.

In fact, interferons are produced in response to PRR signalling triggered by a wide range of PAMPs, but the role of IFNs in response to these diverse pathogens is not as clearly understood as it is for viruses.

Nor are the distinct roles of the many different type I and type III interferons understood.

34
Q

Recap the extracellular roles of antibodies

A
  • opsonisation
  • neutralisation
  • complement activation
35
Q

What are the functions of complement?

What are the different susceptibilities to complement between enveloped and non-enveloped viruses?

A
  • opsonisation (with a positive feedback loop boosting deposition of more complement
  • lysis (pore formation by the membrane attack complex

all viruses are susceptible to opsonisation, but pore formation requires a membrane, so this can only affect enveloped viruses

  • if an enveloped virus fuses with its membrane with the plasma membrane, this also means that opsonins (antibodies or complement) will be left on the cell surface, which might mark it out as potentially infected
36
Q

What happens to invading viruses when antibodies are carried into cells?

When might this happen?

A
  • if a non-enveloped virus is opsonised by an antibody, you might think that escaping into a cell makes it safe, as it has not left membrane on the cell surface
  • however, antibodies carried into cells can direct the destruction of invading viruses, mediated by intracellular Fc receptor TRIM21
37
Q

Describe how the intracellular Fc receptor, TRIM21, destroys invading viruses after antibodies are carried into cells

A
  • As these adenovirus particles flow through the blood, they encounter antibodies, which bind to them and mark them out as alien.
  • The adenovirus particles bind to the cell surface.
  • This triggers their endocytosis.
  • They then escape from the endosome, into the cytoplasm.
  • Next, they begin their journey to the cell nucleus, where they need to replicate.
  • However, the antibody on the virus surface binds to TRIM21, an intracellular antibody receptor.
  • This causes TRIM21 to catalyse the ligation of ubiquitin to itself, forming poly-ubiquitin chains.
  • These chains are signals that recruit the proteasome, the cellular garbage factory.
  • Recruited in this way, the proteasome then begins to degrade the virus proteins into short peptides which disrupts the structure of the virus particle.
  • This not only destroys the virus, but leaves viral DNA in the cytoplasm, where it is a potent PAMP, alerting the cell to the fact that it has been infected.
38
Q

How do viruses evade humoral immune molecules?

A
  • Pathogens have a wide range of strategies for avoiding humoral immune molecules, ranging from ‘lifestyle choices’, where the pathogen travels between cells without being exposed to extracellular fluids, to directly acting against specific humoral molecules.
  • Examples (not assessed, see e-module for more detail):
  • syncitium formation
  • the virological synapse
  • defusing complement
  • avoiding the cytoplasm
39
Q

Where in the cell do peptides for MHC Class I presentation come from?

Are these viral or cellular proteins?

A
  • Peptides for MHC class I presentation come from intracellular (cytoplasmic) proteins.
  • Most of these peptides are produced from proteins as they are being synthesised (translated), often waste products of translation errors.
  • This comprises both cellular and viral proteins.
40
Q

Do MHC Class I and II molecules discriminate between self and non-self peptides?

A
  • no
  • therefore, the process of clonal selection in the thymus must rigorously delete T cells whose receptors can bind to self peptides on MHC molecules.
41
Q

Apart from peptides that originate during protein synthesis, where else do peptides arise from for MHC Class I presentation?

When does this happen?

A
  • some peptides also arise from protein degradation in the cytoplasm
  • for this, a specialised version of the proteasome is required: the immunoproteasome
  • Certain immune processes can push the products of protein degradation to be presented on MHC class I.
  • One example is the degradation of viruses initiated by TRIM21 binding to antibody that we described earlier.
42
Q

How do dendritic cells present proteins to a cytotoxic T cell?

A
  • Exactly how this happens is unclear, but in principle, antigens delivered from other APCs are internalised by DCs, shifted to the cytoplasm, cut up into peptides, and mounted on MHC class I molecules.
  • Depending on the co-stimulatory signals and cytokine environment, this can either activate the CTLs, or – if there are no danger signals – can induce tolerance (so-called ‘cross tolerance’) for self antigens
43
Q

Which innate lymphoid cell is important for the rapid clearance of viral infections?

What do they partner up with?

What happens when humans are low on these cells?

A
  • NK cells (as innate lymphoid cells) are important for the rapid clearance of viral infections, and as we will see, are an important partner of CD8+ T cells which have similar effector functions.
  • Individuals lacking NK cells are particularly vulnerable to a range of viral infections, and to certain virus-associated cancers.
44
Q

Which two cells, one from innate and one adaptive, have conceptually the same process of killing viruses?

A
  • CD8 T cells and NK cells
  • In IMI5 you heard about the strong activation signal produced in CD8 T cells by the specific interaction between the TCR and its target peptide on MHC class I, and how this can be countered by inhibitory receptors like CTLA-4 and PD1.
  • NK cells operate in the same way, but cannot rely on antigen-specific binding.
45
Q

How do NK cells get activated?

A
  • they rely on the target cell to show danger signals: either upregulating ligands that bind to the NK cell’s activating receptors; or down regulating ligands that bind to its inhibitory receptors.
  • the balance of activating and inhibitory signals defines whether the target cell is regarded as safe, or a danger to be destroyed.
46
Q

Describe in detail how NK cells are activated and deactivated

A
  • The activity of NK cells is defined by the balance of inhibitory and activating receptors.
  • Having more inhibitory receptors means that the NK cell tolerates the signal, and does not let loose its destructive weaponry.
  • Ligation of inhibitory receptors to MHC class I on a healthy cell is an important inhibitory signal, resulting in NK cell tolerance (left).
  • The NK cell becomes activated to kill a target cell as soon as MHC class I molecules go missing, as for example on tumour cells, or by a virus attempting to avoid detection.
  • This is called ‘missing self’ recognition (middle).
  • Alternatively, signals of intracellular stress, or intracellular infection can upregulate activating receptors to levels that overwhelm the inhibitory signals (right).
  • When the activating signals to NK cells outnumber the inhibitory ones, then the NK cell goes into action and destroys the offending cell
47
Q

What is the role of MHC Class I in managing NK cell responses?

A
  • MHC class I can play an important role in managing NK cell responses.
  • However, its role is to provide a potent inhibitory signal to NK cells, regardless of what peptide is bound.
  • It is only when MHC class I goes missing from the cell surface that the decision to kill becomes easy to trigger, as a smaller activating signal will be required.
48
Q

NK cells are strongly inhibited by MHC class I so they will need a very strong activating signal to make them kill cells with MHC class I on their surface.

However, they will much more easily kill cells whose MHC class I cells are missing.

Why is this a good anti-viral (and anti-cancer) strategy?

A
  • The answer is a classic example of how the innate and adaptive immune systems complement each other.
  • As shown in the cartoon, a cell with MHC class I molecules allows any infections (or mutations in cancer) to be detected so the cell is destroyed by cytotoxic T cells.
  • Viruses and cancer cells therefore have a strong interest in down-regulating MHC class I on the cell surface, so they do not present antigenic peptides to T cells.
  • Indeed, many viruses have evolved mechanisms to down regulate MHC class I to avoid T cell killing.
  • However, because NK cells use MHC class I as an inhibitory ligand, removing MHC class I makes the infected cell vulnerable to NK cell killing, needing far fewer activating receptors to trigger NK cell activation.
49
Q

What specific antigen does an NK cell need to recognise to be activated?

A
  • NK cells don’t recognise antigen
  • The lack of requirement for antigen is is why they are called natural killer cells.
  • NK cells have inhibitory receptors, such as those that bind to MHC class I loaded with (any) peptide.
  • MHC Class I is not an ‘antigen’ and in any case is not correct because it has an inhibitory effect on NK cells, regardless of whether it contains antigen.
  • The decision to act comes from the sum of activating signals triggered by intracellular immune responses, counteracted by negative signals such as that triggered by the presence of MHC class I.
50
Q

What are the three ways pathogens can avoid the adaptive immune response?

A
  • Changing the pathogen’s antigens so they are different from previous infections
  • Adopting an evasive lifestyle
  • Directly interfering with the generation of an adaptive immune response
51
Q

What is antigenic variation?

A
  • when bacteria can change which gene they are using to make their surface proteins, allowing them to avoid an established antibody response

-

52
Q

Why can’t viruses undergo antigenic variation?

Describe what happens instead and the name for this process

A
  • Antigenic variation in bacteria requires a large coding capacity, as it relies on having many genes for surface proteins, and switching between them.
  • Viruses are too small for this luxury, so instead, they rely on evolution (mutation and diversification) to escape the immune response.
  • The best characterised example of this is influenza virus.
  • As more people become immune to a virus (by seasonal infection or vaccination), there is an increasingly strong selective pressure for viruses to evolve changes in their glycoprotein sequences that are no longer recognised by antibodies that were capable of recognising previous influenza virus strains.
  • This gradual evolution eventually accumulates enough changes to let the virus escape the antibody response long enough to re-infect repeatedly the same individuals.
  • This process is referred to as antigenic drift.
53
Q

What is antigenic shift?

A
  • influenza virus has another strategy that makes it more dangerous in human populations.
  • The natural host for influenza virus is waterfowl (e.g. ducks, geese), but there are various strains that can infect many birds and mammals.
  • First, this means that the virus can evolve in another animal, becoming completely unrecognisable to our existing immunity against seasonal human-adapted strains.
  • Then, when a flu spreads into humans from another species (and if it also has the right adaptations that can counter human innate immune barriers), the new virus can spread unrestrained through the population, because the adaptive immunity in the population does not exist to stop it.
  • It often becomes the dominant strain, representing an antigenic shift, to a completely new immunological profile.
54
Q

Using the Covid pandemic, describe how antigenic shift and antigenic drift comes into place

A
  • Arguably, we are seeing similar phenomena in the SARS-CoV2 pandemic, with emergence of a new virus from an animal reservoir (antigenic shift), amongst which new strains are emerging, in part adapting to spread better in the face of the vaccine induced immunity (antigenic drift).
55
Q

Describe virus latency

A
  • Rather than rapidly spreading and changing, some pathogens have taken the slow road, establishing a persistent infection whose strategy allows it to hide from surveillance by CD8 T cells (eg virus latency).

An example is given below to help you understand this idea, but you will not be expected to know the details.

56
Q

Give examples of how viruses can disrupt immune responses (over avoiding the immune system)

A
  • viral superantigens:
  • IMI6 described the action of superantigens - proteins that trigger T cell activation in an indiscriminate way. Remind yourself of this if you have forgotten it.
  • There is evidence that a number of viruses, including Epstein-Barr virus, Rabies and SARS-CoV2 also have mechanisms to drive the indiscriminate activation of T cells.
  • infecting and killing or dysregulating immune cells:
  • An alternative approach to delaying the generation of an immune response is to directly infect and kill the cells involved in mounting that response.
  • You saw this most spectacularly in the IMI3 F2F for measles virus, but plenty of pathogens have lifecycles that target B cells, T cells, macrophages or dendritic cells for infection, a process that may delay the generation of an effective immune response (although this hypothesis is very difficult to prove!).
  • MHC Class I Down-regulation:
  • Perhaps the most common trick used by viruses to avoid destruction by T cells is to prevent the function of MHC class I molecules.
  • Many viruses encode mechanisms for degrading MHC class I, or sequestering it in endosomes, rather than at the cell surface, although we now know this makes the cell vulnerable to NK cells, so the virus would need a way of getting around this too…
57
Q

Which four of these immunological processes, molecules or cells are most important for controlling infection by intracellular pathogens?

A
  • MHC Class I antigen presentation
  • natural killer cells
  • cytotoxic T cells
  • intracellular PRRs
58
Q

How does the transcriptional strategy of latency (shutting down transcription of viral protein-coding genes) evade immune surveillance?

What is the mechanism by which the virus evades this?

A
  • CD8+ T cells cannot detect viral antigens
  • the virus makes no proteins to be presented on MHC Class I
59
Q

For what reason(s) might inhibiting complement help an enveloped virus?

A
  • To prevent opsonisation of the virus or infected cell
  • To prevent the formation of a membrane attack complex destroying the virus particle

Complement does not attract antibody (though antibody can attract complement).

Any surface complement will not enter a cell, as the viral membrane is left at the cell surface, so an intracellular complement receptor (if such a thing existed) could only affect non-enveloped viruses.

However, it could play a role in opsonising the cell as well as the virus, and if complement facilitated MAC formation, it could destroy infectious virus particles.

60
Q

Summarise the mechanism cells use to handle intracellular responses

A
61
Q

Summarise the ways pathogens can counter these activities

A
62
Q

What characteristics of the virus define the detection mechanism?

A
  • genome
  • envelope
  • location in cell
  • acute vs chronic vs latent