viral infections Flashcards
interferon: list the types of interferon, recall the cell types that produce them, explain how interferon synthesis is regulated, explain the role of type I interferon stimulated genes, recall examples of viruses controlling or evading type I interferon and explain how this can direct new therapy development, and summarise the canonical type I interferon signaling pathway
describe 3 stages of immune response to viruses
intrinsic (e.g. skin, mucous membranes etc.) -> innate immunity (within hours, no specificity) -> acquired immunity (specific)
describe presence of CpG in intrinsic immunity to viruses
different ratio of nucleotides (high CpG) seen as foreign and degraded by RNA exosome
what is interferon
soluble protein made by cellls infected by virus, and spreads to neighbouring cells
what does interferon bind to on neighbouring cells, and what is the signal outcome
binds to specific receptors and signals activation of de novo transcription of hundreds of interferon stimulated genes (ISGs) to prevent infection by virus
what are type 1 interferons and what are they secreted from
polypeptides secreted from infected cells
3 major functions of type 1 interferons
induce antimicrobial state in infected and neighbouring cells, modulate innate response to promote antigen presentation and natural killer, activate adaptive immune response
describe type 1 interferon pathway in infection
virus recognised by infected cell -> release interferon B -> binds to neighbouring cell receptors -> switches on ISGs -> causes response in APCs, B cells, T cells, NK cells etc.
2 subtypes of type 1 interferons
interferon a, interferon B
describe secretion and induction of interferon B
secreted by all cells, with IFNAR receptor present on all tissues; interferon B induction triggered by IRF-3
describe secretion of interferon a
plasmacytoid dendritic cells (PDCs) are specialist interferon a secreting cells
what do PDCs express high levels of constitutively
IRF-7 (transcription factor which stimulates transcription of interferon a)
describe genes and isotypes for interferon B vs interferon a
one gene for interferon B, 13/14 isotypes of interferon a
what type of interferon is type 2 interferon
interferon y
what cells produce interferon y
activated T cells and NK cells
what receptor do interferon y signal through
IFNGR
what type of interferon is type 3 interferon
interferon λ
what cells do interferon λ signal through
epithelial surfaces, so important in early infection, as well as liver cells (doesn’t affect immune cells)
what 2 liver viruses are polymorphisms in interferon λ associated with improved outcomes
improved outcome from hep C and hep B (both spontaneous clearance and response to antiviral therapy)
how do cells differentiate between self from non-self
look out for pathogen associated molecular patterns (PAMPs) on pathogens (e.g. viral genome) using pattern recognition receptors (PRRs)
3 pathogen recognition receptors which sense foreign nucleic acid (PAMPs)
cytoplasmic RIG-I like receptors (RLRs), endosomal toll-like receptors (TLRs), cytoplasmic nucleotide oligomerisation domain receptors (NLRs)
what do RIG-l and/or MDA-5 in RLRs bind to, and what is the effect pathway
bind to viral RNA -> change conformation to bind to MAVS on mitochondial membrane -> change conformation and cause downstream cascades -> phosphorylates IRF-3 (dimerises and acts as transcription factor for interferon B) -> interferon B produced
in dendritic cells, what does TLR-3 in endosome bind to, and what is the effect pathway
bind to viral RNA, and same pathway as RIG-l, so phosphorylate IRF-3 and lead to transcription of interferon B
in dendritic cells, what do TLR-7 and 8 in endosome bind to, and what is the effect pathway
bind to viral RNA -> bind to Myd88 -> downstream pathways to activate IRF-7 (constitutively expressed in dendritic cells) -> production of interferon a
in cytoplasm, what do cGAS bind to, and what is the effect pathway
bind to viral DNA -> activate cGAS enzyme -> makes cGAMP -> bound by STING on endoplasmic reticulum membrane -> cascade causing phosphorylation of IRF-3 -> interferon B production
describe signalling of interferon B following production
production and release of IFN-B -> binds to receptor on infected (autocrine) and neighbouring (paracrine) cells -> promotes transcription of ISGs -> antiviral signals
what genes can have mutations affecting interferon production
IRF-7, IRF-3, IFNAR2 (receptor)
describe prevalence and high risk patients of herpes simplex encephalitis (HSE)
most common cause of sporadic encephalitis (inflammation of brain) in Western world, and most common in childhood (affect previously healthy individuals on primary infection with herpes virus)
effect of 6 genes (including TLR-3 and IRF-3) with inborn errors implicated in HSE
impair CNS intrinsic interferon a/B response to herpes virus infection
what does interferon induce when binding to INFAR1 and 2
promotes cascade involving JACK and STAT which causes transcription of hundreds of antiviral mediator genes
interferon stimulated genes: effect of PKR
transiently inhibits translation (prevent viruses translating as well)
interferon stimulated genes: effect of 2’5’OAS
activates RNAse L that destroys ssRNA (destroy all messenger RNA proteins)
interferon stimulated genes: effect of Mx
inhibits incoming viral genomes
interferon stimulated genes: effect of ADAR
induces errors during viral replication
interferon stimulated genes: effect of serpine
activates proteases
interferon stimulated genes: effect of viperin
inhibits viral budding
what does IFITM3 do
restrict virus entry through endosomes by fusing with endosomal membrane and preventing release of virus (if lack IFITM3, get more severe influenza)
what can Mx form, and what do these do
multimers, which wrap around nucleocapsids of incoming viruses
what virus does Mx1 inhibit
influenza
what virus does Mx2 inhibit
HIV
effect on interferon response by cells in antiviral state after self regulating to limit damage
only maintain interferon response for several hours, so ability to respond to interferon is lost due to negative regulation
what genes turn off response
SOCS (suppressor of cytokine signalling) genes
7 different strategies by which viruses evade interferon response
avoid detection by hiding PAMP, interfere globally with host cell gene expression and/or protein synthesis, block interferon induction cascades by destroying or binding, inhibit interferon signalling, block action of individual interferon-induced antiviral enzymes, activate SOCS, replication strategy that is insensitive to interferon (very fast)
interferon control by viruses to stop activation: hep C
NS3/4 protease acts as antagonist to interferon induction by cleaving MAVS from mitochondrial membrane
interferon control by viruses to stop activation: influenza
NS1 protein acts as antagonist to interferon induction by binding to RIG-I/TRIM25/RNA complex, preventing activation of signalling pathway (also prevents nuclear processing of newly induced genes)
significance of large DNA viruses e.g. pox and herpes
much of genome is comprised of accessory genes to modify immune response, which prevent signal getting through (e.g. encode soluble cytokine (interferon) receptors - being developed as posible future immune therapies)
2 ebola virus immune evasion mechanisms
stops being sensed, VP24 prevents interferon production by other cells
viral pathology as consequence of innate immunity
combination of damage of infected cells by virus, and damage of infected and bystander cells by immune response, causing lethargy etc.
how do viruses skew immune response to increase own replication and transmission
interfere with interferons, resulting in protective effects to immunopathologic effects (depending on how much interferon is made)
how does innate immunopathology of virus infections result in cytokine storm
as viruses replicates, it induces high interferons, accompanied by massive TNFa and other cytokines (e.g. IL-6, IL-1)
what can differences in clinical outcome of cytokine storm reflect
vigour of innate immune system (varies with age - typical of Dengue haemorrhagic fever, severe infleunza infections and Ebola)
describe cytokine storm
infected cells are making interferon but aren’t limiting replication of virus, so more interferons and inflammatory mediators are made, causing more damage to cells
3 consequences of cytokine storm
make endothelium leaky, stimulate inappropriate inflammatory response, trigger pulmonary fibrosis
4 consequences of balance between viruses and interferons
host range barriers, therapeutics, vaccines, oncolytic vaccines
consequence of using interferon as an antiviral treatment
associated with unpleasant side effects as activates many pro-inflammatory pathways
describe use of interferon λ as an influenza therapeutic
signals to epithelial cells, which don’t recruit immune cells but simply cause neighbouring cells to enter anti-viral state (prevent cytokine storm)
how are viruses deficient in control of interferons (either naturally or engineered) used in treatment
make poor viruses as cleared quickly, so attenuated in interferon competent cells for live attenuated vaccine (high interferon levels they induce can also recruit useful immune cells)
describe use of oncolytic viruses as cancer treatment
interferon deficient state of cancer cells, so kill cancer cells but not healthy cells
