Module 1 Flashcards
(51 cards)
1
Q
What is a virus
A
- Nano-scale sub-microscopic entity composed of genetic info contained in a protein particle
- obligate intracellular parasites
- not alive
- can cause disease in host
- can change phenotype via mutations
- symmetrical
2
Q
Viral assembly
A
- occurs intracellularly using ATP, biosynthetic capabilities and physical structures
- assemble to acquire their mature form
- lipid envelope derived from host membrane
3
Q
Which viruses lack a envelope
A
those found in the gut as low pH creates lipid instability
4
Q
Virus encoded transmembrane proteins
A
- often form spikes that mediate attachment to cell surface receptors
- allows for raft formation to pick up encoded proteins
5
Q
Viral genomes
A
- dsDNA, utilises hosts DNA pol for replication
- ssDNA+, convert to dsDNA then use DNA pol
- dsRNA, RNA polymerase from virus
- ssRNA, reverse transcriptase to convert to dsDNA, use host cell Pol
6
Q
Virus evolution
A
- high mutation rates in viral genomes means a higher frequency of mutation allowing for rapid evolution
- contributes to antibiotic resistance and spillover from animals
7
Q
Wolfe et al stages of transformation from an animal pathogen into a specialised human pathogen
A
- 1 = microbe present in only animals
- 2 = animal pathogen transmitted to humans under natural conditions (rabies)
- 3 = animal pathogens that can be passed from human to human sometimes (ebola and monkeypox)
- 4 = disease in animals which has a natural cycle of infecting humans and long secondary transmission (Influenza)
- 5 = pathogen exclusive to humans (HIV and Measles)
8
Q
Stages of the viral replication process
A
- Attachment
- Entry
- Replication and gene expression
- Assembly
- Release
9
Q
Attachment
A
- Requires a chemical attraction (receptors) leading to the binding of the virus
- Attach to low affinity ubiquitous cell surface molecules (glycoproteins) and then a high affinity second receptor which drives conformational changes
10
Q
Entry
A
- Enters via conformational changes such as membrane curvature
- virus is broken down into components allowing for replication and viral protein synthesis
11
Q
Assembly
A
cell assembles viral genome and proteins into a new viral particle which can then be released
12
Q
Release
A
Infect cell may lyse or virus may exit via budding
13
Q
How is the process of infection studied
A
- mammalian cell cultures using primary or transformed cells
14
Q
SARS-COV2 interactions to attach and enter cells
A
- uses the ACE2 receptor and TMPRSS2
- TMPRSS2 causes cleavage of the viral spike protein to allow rapid entry
15
Q
Acute infection
A
- Self-limiting period where a virus reaches its peak and then disappears
- most viral infections are acute
16
Q
Recurrent infection
A
- usually acute infections affecting individuals with an impaired immune response
17
Q
Slow infection
A
- slow replication
18
Q
Late infection
A
- infects but then becomes latent
- can be reactivated later
19
Q
Why most viral infections are acute
A
the human immune system counteracts the cytopathic effect thus limiting the infection via its removal
20
Q
Innate immunity
A
- First line of defence
- recognises foreign material via PRRs
- PRR activation leads to the production of IFN and cytokine release
- IFN induces a phenotypic change in infected cells and those in proximity to block viral replication to induce an antiviral state
- activates interferon stimulated genes which suppress viral replication and mediate an antiviral state
- dendritic cells bind cytokines and take up viral proteins, produce more cytokines to amplify the response
- NK cells secrete molecules which act on cells in proximity
21
Q
PRRs
A
- recognise cytoplasmic and endosomal DNA
- RLRs - recognise and bind to RNA with a 5’ triphosphate
- RIG-1 - recognise ssDNA
- MDAS - recognise dsRNA
- TLRs - sense viral glycoproteins, dsRNA, ssRNA and CpG
22
Q
PRR signalling
A
- Once the PRR has detected a virus it will cause a signalling cascade
- a series of transcription factors such as IRF3 become phosphorylated upon activation of PRR driving IFN expression
- IFN causes a phenotypic change
- ISG production
23
Q
Natural killer cell pathways
A
- cytokines
- antibodies
- Induced self ligand
- virus derived ligand
24
Q
NK activation balance
A
- uninfected cells produce inhibitory signals protecting against NK cell activity
- infected cells are killed
- if overexpressed can lead to inflammation which is why these are put in place
25
Adaptive immunity
- slower response dependent on innate process which activate APC
- occurs if viral replication out competes innate defences
- humoral and cell-mediated responses
- works on precise chemical signatures in a specific virus
- T and B cells
- Antibodies bind to virus particles to lock viral attachment thus the spread of infection
- memory response obtained
26
T cells
- CD8 = recognise viral peptides presented on infected cells via MHC class I
- CD 4 = recognise viral peptides presented on MHC class II on the surface of APC, produce antiviral cytokines and chemokines
27
Experimental evidence for immunity
- can measure the amount of virus and RNA levels present with IFN addition vs control
- KO IFN receptors and measure survival rate upon infection
- Loss of IFNAR1 function caused individuals with measles vaccine to become sick
- Can screen B cells which encode for proteins against a specific virus
28
Viral evasion strategies
- Hiding the viral genome
- Inhibiting host inducers of IFN
- Regulating phosphorylation events
- Regulating ubiquitinylation and related pathways
- Cleavage and degradation
- Transcriptional shut off
- RNA processing and trafficking regulation
- Translational shut off
- Decoys
29
Immune evasion - hiding the genome
- Avoid cytoplasmic detection of viral nucleic acids
- Vaccinia virus - generates viral factories which exclude cellular nucleic acid sensors
- genome encapsidation avoiding recognition
- modification of 5' triphosphate to avoid RIG-1
30
Immune evasion - inhibiting interactions with host inducers of IFN
- inactivation of downstream cellular factors preventing IFN signal transduction
- Herpesvirus - protein binds to activated IRF3 preventing its transcription
31
Immune evasion - regulating phosphorylation events
- Viruses target kinases and phosphatases to inhibit IFN signalling
- RIG-I and MDA5 sensors are inactive when phosphorylated
32
Immune evasion - regulating ubiquitinylation and related pathways
- Viruses alter ubiquitination to inhibit IFN signalling
- can block E3 ligase activity thus RIG-I cannot be activated
33
Immune evasion - cleavage and degradation
- viral proteases cleave host proteins important for the IFN response
34
Immune evasion - transcriptional shut-off
- inhibit transcription of IFN and ISG expression
- Adenovirus E1A protein prevents chromatin from opening up
35
Immune evasion - RNA processing and trafficking regulation
- viruses can prevent host gene expression via posttranscriptional inhibition of cellular RNA processing and trafficking
- KSV protein inhibits mRNA export
36
Immune evasion - Translational shut off
- Can induce general or selective translational inhibition
- Hep C - promotes PKR activation to inhibit translation of antiviral effector proteins
37
Immune evasion - Decoys
- viruses use decoy proteins to sequester host factors
- Poxvirus-encoded soluble IFN receptors sequester IFN
38
What is PKR
an interferon stimulated gene which contributes to the antiviral state of a cell
39
PKR substrate
- Eif2a
- phosphorylates Eif2a causing inhibition of viral protein synthesis leading to apoptosis
- binds dsRNA
40
Immune evasion - Non structural proteins
- inhibit the action of ISGs and PRR signalling
- SARS-CoV-2 NSP inhibits polyubiquitination and aggregation of MAVS repressing the release of IFN-B
41
Immune evasion - neutralising antibodies
- viruses can have amino acid mutations that neutralise antibodies thus making adaptive immunity ineffective
42
SARS-COV-2 immune evasion techniques
- NSP that inhibits polyubiquitination and aggregation of MAVS, repressing IFN-B release
- escapes NK cell killing via downregulation of ligands for NKG2D
43
What is pathogenesis
the process by which disease develops
44
What is virulence
the severity of disease caused/the capacity of a virus to cause disease in an infected host
45
Rotavirus
- Transmitted via faecal oral route
- symptoms = stomache ache etc
- acute self-limiting infection
- infects mature/differentiated epithelial cells located at the villous tips in the small intestine
- infected absorptive enterocytes are killed causing patchy epithelial cell destruction and villous shortening
- destroyed absorptive cells are replaced by cells which migrate from crypts causing villi to be temporarily covered with non-absorptive secretory cells
- as they are non-absorptive it causes an efflux of water into the lumen = diarrhoea
- Virus-encoded NSP4 is secreted from infected enterocytes and acts as a pro-inflammatory stimulus in the intestine
- can suppress IFN but not the adaptive immune response
46
Systemic infection
spread of virus from site of primary infection via blood/lymph to secondary sites
47
Viremia
virus present in the blood
48
Measles
- Systemic infection
- pathogenesis is determined by receptor usage
- Can replicate in multiple types of cells via selective receptor usage = Nectin-4 on epithelial cells, SLAM on leukocytes
- Dual receptors permits the systemic infection and transmission to multiple tissues
- high production of cytokines in the blood leads to endothelial cell adhesion loss = loss of vasculature integrity =rash
- Have P/C/V in their genome which allows for immune evasion
49
Influenza
- cytokine mediated disease
- upregulates IFN so much that it becomes toxic to cells
- IFN deletion mutant in models were protective and showed a less severe disease
- Co-pathogenesis during influenza by secondary bacterial infection = large amount of immune infiltrates
50
Ebola
- filovirus
- multiple sites of productive infections = an infect many different tissues
- can use multiples different types of receptors
- primarily infects lymphoid cells = overexpressed cytokines = toxic effect
- infects hepatocytes and endothelial cells = loss of vascular integrity = bleeding
- has multiple immune avoidance mechanisms mediated by Nsp
51
Ebola immune evasion mediated by Nsp
- VP35 and VP30 prevent RNAi action by protecting dsRNA
- VP24 disrupts the IFN receptor at the cell surface
