Immunity Flashcards
What is the function of innate immunity?
immediate response
- prevents infection
- blocks infection/ stops virus spread
- decelerates virus infection: gain of time for adaptive immunity
What is the function of adaptive immunity?
- full recovery
- protection against reinfection
- immunopathology
- auto immunity
- co existence
What type of immune responses are there against viruses?
- induction of interferon (innate, unspecific)
- proliferation of T-killer cells (axquired, specific)
- proliferation of b cells (acquired, specific)
Name the types of active components of the innate immune system
- present components: physical barrier, cells of defense (NK. macrophages), chemical substances
- inducible components/humoral signaling molecules: interferons, chemokines, cytokines
Name the types of interferons. What are their properties?
- interferon type I: alpha (leucocytes), beta (fibroblasts) –> signalling via IFN-alpha receptor
- interferon type II: gamma /Tcells/NK cells) –> signalling via IFN-gamma
- interferon type III
How can interferon type I expression be induced?
- bacterial elements
infection with viruses, especially dsRNA
What are the consequences of interferon type I induction?
- induction of gene expression (of genome, selective transcription, regulation of transcription)
- antiviral state of cell
How do plaques look like after IFN treatment in cell culture?
without IFN: plaque formation (no cells = no stain)
with IFN: no plaques
How are IFN-beta promotors induced?
PAMP receptor recognize infection –> adapter and kinases activated –> transcription factors NF-kB and IRF-3 activated
name viral PAMPs?
- uncapped ssRNA
- dsRNA
- DNA
How does viral dsDNA trigger an immune response?
viral dsDNA binds to cGAS (nucleotidyl transferase) -> stimulation of synthesis of cGAMP –> STING is an ER located stimulator of IFN genes –> STING activates TANK-binding kinase TBK1) –> TBK1 phosphoryltes IRF3
How is intracellular dsRNA detected by the cell?
- via proteinkinase R that is constitutively expressed within many cell types. PKR has two dsRNA bindig motifs –> binding of dsRNA leads to autophosphorylation and so activating PKR –> active PKR leads to activation of NF-kB
- RIG I (recognizes uncapped RNA, short blunt regions and poly uridine stretches)
- MDA 5: recognizes longer dsRNA
–> RIG I and MDA 5 bind to IFN beta promotor stimulator in mitochondria (= mitochondrial antiviral signaling MAVS) –> actiavtes NF-kb and IRF3, but also some MAVS localize to Peroxisome for a short term antiviral response
Which structure in RIG-I senses viral RNA? and how?
c- terminal regulatory domain:
- binds viral RNA in a 5’ trophosphate- dependent manner
- activates the RIG-I ATPase by RNA dependent dimerization
- 2 CARD domains transmit the signal
How can RIG-Idiscriminate between pathogenic from self RNA?
RIG I recognizes:
- 5’ PPP RNA
- short ds RNA
- ssRNA hairpins
–> ATP powered dsRNA translocation occurs preferentially on dsRNA and in the absence of 5’ triphosphare the CARD domain suppresses translocation
For what are MAVS (mitochondrial antiviral signaling) essential?
for sustained anitiviral effect
How can RIG I and MDA5 mediate the activation of IFN- beta promotors after recognition of viral RNA?
- dsRNA binds to helicase domain of RIG-I
- ATP hydrolysis
- conformational change
- ubiquitinilation via TRIM25
- CARD can now interact with adaptor molecule (e.g MAVS –> only in mitochondria –> translocation to mitochondria mediated by 14-3-3-epsilon )
- TBK1 mediated activation of IRF-3 (in nucleus)
- activation of IFN gamma promotor
What is essential for the signalling activity of RIG-I?
ubiquitination of RIG-I
What role does LGP2 play?
is a positive regulator of RIG-I and MDA5
which virus families are recognized by RIG-I and/or MDA5?
both:
- -ssRNA: paramyxoviridae
- +ssRNA: Flavi, Corona
- dsRNA
- dsRNA of DNA viruses: Herpes, Adeno
only MDA5
- +ssRNA: Picorna, calci
only RIG-I:
- -ssRNA: Filo, Rhabdo, Orthomyxo, Nunya, Arena
- dsRNA: Epstein bar
Which viruses can escape a RIG-I or MDA5 recognition (RLR recognition)?
- Bunya
- borna
- corona
- arena
How do the cRNA and vRNA of NSV differe from mRNA?
cRNA and vRNA have a triphosphate group at their 5’ end which can be recognized by the immune system whereas the mRNA has a 5’ cap
Which strategies do plus strand RNA viruses use gainst IFN induction?
- hiding of dsRNA in membrane vesicles
- cleavage of signalling molecules by viral proteases
which strategies fo minus strand RNA viruses use against IFN induction?
processing of genome 5’ terminihj
what does control the tolerance pf RIG-I to N1-2’O methylated self RNA?
a consereved histidine in RIG-I
what does TLR-3 recognize?
extracellular dsRNA
Name TLR that detect viral nucleic acids
- TLR 7/8
- TLR 3
- TLR 9
what is induced by TLR signaling after recognition of viral nucleic acid?
IFN alpha or beta
Name interferon induced antiviral proteins
- PKR-P: block of protein synthesis
- RNase L: mRNA decay
- Mx GTPase oligomers (assembling to aggregates leads to antiviral form): binding to nucleocapsids
- IFIT1: binds and sequesters RNAs with 5’PPP
- ZAP: binds to N-term. of RNA and forms stress granules (degradation)
Explain the interferon alpha/beta system
- virus infection leads to induction of interferons via IRF-3, IRF-9 or NF-kB
- interferons are released from the infected cells
- IFNAR of another cell (not infected) recognizes interferons
- signalling cascade via JAK/STAT anf IRF 9
- expression of antiviral proteins
Name an RNase L antagonist in coronavirus
ns2 protein via phosphodiesterase activity
Explain the mode of action of Mx in Orthomyxovirus
- viral RNA is replicated in nucleus
- transport of viral nucleoprotein complex into the nucleus which is essential for viral replication
–> mx binds the nucleoportein complex in the cytoplasm and thereby inhibits its transport into the nucleus –> block of viral replication
explain the mode of action of mx viruses in bunyavirus
viral RNA is replicated in golgi –> proteins are translocated into the cytoplasm –> mx binds to the viral N protein and inhibits its transport into the golgi apparatus –> block of viral replication
explain the mode of action of interferon induced antiviral protein ZAP
ZAP binds to RNA via n-terminus with cofactor PAR –> Par facilitates formation of non-membranoues sub-cellular compartments which lead to the degradation of viral RNA in those stress granules
And which point can viral interferon antagonist inhibit the interferon system?
- block of IFN induction: block of interferon receptors of uninfected cells or blocking IRF3/9
- block of IFN signalling
- block of IFN effect: interception/blocking of mx, PKR
How does influenza avaoid recognition by RIG-I?
NS1 specifically inhibits ubiquitin ligase TRIM25–> RIG-I CARD cannot be ubiquitinilated –> suppression of RIG-I signal transduction
How does dengue avoid interferon mediated responses?
NS3 interacts with 14-3-3-epsilon which is essential for the ubiquitinilation of RIG-1 by ubiquitinligase TRIM25 –> RIG-I cannot be targeted to mitochondria because transfer of RIG-I to MAVS is blocked
What is one reason for some severe covid cases?
due to a misfunction in the innate immune system
- neutralizing autoantibodies against type I IFNs
- deleterious variants in IFN type I genes that can impair gene function
–> central role of innate immune cells/immunity in clearance of SARS CoV-2 with out severe cases
which strategies are used by BVDV for persistence?
- N-terminal protease: binds to IRF3 –> no interferon synthesis in infected cells
- envelope protein ribonuclease secreted: RNase activity –> binds dsRNA and blocks IFN induction by free dsRNA
Which proteins block innate immunesytem in Pestivirus and Hepacivirus?
pesti: N^pro and E^rns
hepaci: NS3/4A
How does HCV persists?
NS3/4A cleaves
- TRIF –> no signalling via TLR 3 or 4
- Cardif (MAVS)
Do all viruses encode IFN antagonists?
yes
Describe the kinetics of the antiviral immune response? which factors are first activated, which last?
from first to last:
- IFN
- NK
- cytotoxic t cells (week)
- antibodies (weeks)
Which viral immune evasion startegies are used in lytic, latent and persistent infection?
lytic: blocking IFN
latent: providing no target
persistent: immune tolerance (no response) or immune evasion via adaption to b and t cell response or block of immune response
describe the loading of MHC class I with antigen
- uptake of virus: endocytosis and delivery to endosome
- fusion of virus with endosome membrane and escape of viral RNA into cytosol
- replication and translation of viral RNA into RNA and intzernal viral proteinS (=antigens)
- proteolysis of some viral protein molecules by proteasome
- proteasome shreeds proteins into peptides
- transport of peptide into ER lumen
- binding of peptide to fitting MHC1 (to alpha chain)
- transport to golgi
- transport of class I MHC protein with bound peptide trough celll surface
- recognition by cytotixic t cell
How do different viruses evade the MHC complex formation?
- HIV: vpu –> block of MHC assemblky
- HSV: block of peptide transport in to ER
- adenovirus and HIV Tat: reduction of transcription of MHC I genes
- Adenocvirus: ER3 –> block of MHC transport out of ER
- HIV nef –> transport of MHC into lysosome
How does loading of MHC II with antigen work?
- endocytosis and delivery to endosome of virus
- late endosome: limited proteolysis of protein antigen and of invariant chain
- leaving of fragment of invariant chain in binding grove of MHC protein
- HLA-DM protein catalyzes release of invariant chain fragment and binding og antigen derived peptide (in endsome)
- delivery of peptide calls II MHC complex to plasmamembrane
- recognition by helper t cell
What is the difference between MHCI and MHCII? Why is it important for vaccines?
for MHC II no active viral protein production needed –> important for vaccines that are not life vaccines
What is the role of viroceptors and virokines in pox infection?
theya re immunomodulators and regulators of apoptosis:
- viroceptos: bind cyto/ chemokines (decoy)
- virokines: secreted agonists or antagonists for cell
What is the base of immunity in plants/invertrevrate cells and vertebrate cells?
plants: RNA based –> RNA interference via RISC
vertebrates: protein based: Interferons
How were resistance through cellular restriction factors identified?
different strains of mice and different cells in cell culture differ in their permissiveness –> restriction by crossbreading or cell fusion transferable to a permissive system
How does the intrinsic antiviral factor SAMHD1 work? Name its antagonist
- hydrolyzes intracellular dNTPs –> lowering concentration below the level of dNTPs needed for synthesis of viral RT
- antagonist: Vpx
Name factors tha play a role in resistance through host factors. How are they antagonized?
- Fv1: FV1 gene defect leads to sensitivity to MLV in mice
- tetherin: inhibites retrovirus release <– HIV vpu
- APOBEC1: leads to hypermutation in retroviral cDNA <– HIV-1 vi
What role does tetherin play? how is it antagonized?
- inhibits retrovirus release
- antagonized by HIV vpu
