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Y2 MCD Microbiology > viral infections > Flashcards

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

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Biology 101 flashcards
1
Q

describe 3 stages of immune response to viruses

A

intrinsic (e.g. skin, mucous membranes etc.) -> innate immunity (within hours, no specificity) -> acquired immunity (specific)

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2
Q

describe presence of CpG in intrinsic immunity to viruses

A

different ratio of nucleotides (high CpG) seen as foreign and degraded by RNA exosome

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3
Q

what is interferon

A

soluble protein made by cellls infected by virus, and spreads to neighbouring cells

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4
Q

what does interferon bind to on neighbouring cells, and what is the signal outcome

A

binds to specific receptors and signals activation of de novo transcription of hundreds of interferon stimulated genes (ISGs) to prevent infection by virus

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5
Q

what are type 1 interferons and what are they secreted from

A

polypeptides secreted from infected cells

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6
Q

3 major functions of type 1 interferons

A

induce antimicrobial state in infected and neighbouring cells, modulate innate response to promote antigen presentation and natural killer, activate adaptive immune response

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7
Q

describe type 1 interferon pathway in infection

A

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.

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8
Q

2 subtypes of type 1 interferons

A

interferon a, interferon B

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9
Q

describe secretion and induction of interferon B

A

secreted by all cells, with IFNAR receptor present on all tissues; interferon B induction triggered by IRF-3

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10
Q

describe secretion of interferon a

A

plasmacytoid dendritic cells (PDCs) are specialist interferon a secreting cells

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11
Q

what do PDCs express high levels of constitutively

A

IRF-7 (transcription factor which stimulates transcription of interferon a)

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12
Q

describe genes and isotypes for interferon B vs interferon a

A

one gene for interferon B, 13/14 isotypes of interferon a

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13
Q

what type of interferon is type 2 interferon

A

interferon y

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14
Q

what cells produce interferon y

A

activated T cells and NK cells

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15
Q

what receptor do interferon y signal through

A

IFNGR

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16
Q

what type of interferon is type 3 interferon

A

interferon λ

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17
Q

what cells do interferon λ signal through

A

epithelial surfaces, so important in early infection, as well as liver cells (doesn’t affect immune cells)

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18
Q

what 2 liver viruses are polymorphisms in interferon λ associated with improved outcomes

A

improved outcome from hep C and hep B (both spontaneous clearance and response to antiviral therapy)

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19
Q

how do cells differentiate between self from non-self

A

look out for pathogen associated molecular patterns (PAMPs) on pathogens (e.g. viral genome) using pattern recognition receptors (PRRs)

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20
Q

3 pathogen recognition receptors which sense foreign nucleic acid (PAMPs)

A

cytoplasmic RIG-I like receptors (RLRs), endosomal toll-like receptors (TLRs), cytoplasmic nucleotide oligomerisation domain receptors (NLRs)

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21
Q

what do RIG-l and/or MDA-5 in RLRs bind to, and what is the effect pathway

A

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

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22
Q

in dendritic cells, what does TLR-3 in endosome bind to, and what is the effect pathway

A

bind to viral RNA, and same pathway as RIG-l, so phosphorylate IRF-3 and lead to transcription of interferon B

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23
Q

in dendritic cells, what do TLR-7 and 8 in endosome bind to, and what is the effect pathway

A

bind to viral RNA -> bind to Myd88 -> downstream pathways to activate IRF-7 (constitutively expressed in dendritic cells) -> production of interferon a

24
Q

in cytoplasm, what do cGAS bind to, and what is the effect pathway

A

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

25
Q

describe signalling of interferon B following production

A

production and release of IFN-B -> binds to receptor on infected (autocrine) and neighbouring (paracrine) cells -> promotes transcription of ISGs -> antiviral signals

26
Q

what genes can have mutations affecting interferon production

A

IRF-7, IRF-3, IFNAR2 (receptor)

27
Q

describe prevalence and high risk patients of herpes simplex encephalitis (HSE)

A

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)

28
Q

effect of 6 genes (including TLR-3 and IRF-3) with inborn errors implicated in HSE

A

impair CNS intrinsic interferon a/B response to herpes virus infection

29
Q

what does interferon induce when binding to INFAR1 and 2

A

promotes cascade involving JACK and STAT which causes transcription of hundreds of antiviral mediator genes

30
Q

interferon stimulated genes: effect of PKR

A

transiently inhibits translation (prevent viruses translating as well)

31
Q

interferon stimulated genes: effect of 2’5’OAS

A

activates RNAse L that destroys ssRNA (destroy all messenger RNA proteins)

32
Q

interferon stimulated genes: effect of Mx

A

inhibits incoming viral genomes

33
Q

interferon stimulated genes: effect of ADAR

A

induces errors during viral replication

34
Q

interferon stimulated genes: effect of serpine

A

activates proteases

35
Q

interferon stimulated genes: effect of viperin

A

inhibits viral budding

36
Q

what does IFITM3 do

A

restrict virus entry through endosomes by fusing with endosomal membrane and preventing release of virus (if lack IFITM3, get more severe influenza)

37
Q

what can Mx form, and what do these do

A

multimers, which wrap around nucleocapsids of incoming viruses

38
Q

what virus does Mx1 inhibit

A

influenza

39
Q

what virus does Mx2 inhibit

A

HIV

40
Q

effect on interferon response by cells in antiviral state after self regulating to limit damage

A

only maintain interferon response for several hours, so ability to respond to interferon is lost due to negative regulation

41
Q

what genes turn off response

A

SOCS (suppressor of cytokine signalling) genes

42
Q

7 different strategies by which viruses evade interferon response

A

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)

43
Q

interferon control by viruses to stop activation: hep C

A

NS3/4 protease acts as antagonist to interferon induction by cleaving MAVS from mitochondrial membrane

44
Q

interferon control by viruses to stop activation: influenza

A

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)

45
Q

significance of large DNA viruses e.g. pox and herpes

A

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)

46
Q

2 ebola virus immune evasion mechanisms

A

stops being sensed, VP24 prevents interferon production by other cells

47
Q

viral pathology as consequence of innate immunity

A

combination of damage of infected cells by virus, and damage of infected and bystander cells by immune response, causing lethargy etc.

48
Q

how do viruses skew immune response to increase own replication and transmission

A

interfere with interferons, resulting in protective effects to immunopathologic effects (depending on how much interferon is made)

49
Q

how does innate immunopathology of virus infections result in cytokine storm

A

as viruses replicates, it induces high interferons, accompanied by massive TNFa and other cytokines (e.g. IL-6, IL-1)

50
Q

what can differences in clinical outcome of cytokine storm reflect

A

vigour of innate immune system (varies with age - typical of Dengue haemorrhagic fever, severe infleunza infections and Ebola)

51
Q

describe cytokine storm

A

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

52
Q

3 consequences of cytokine storm

A

make endothelium leaky, stimulate inappropriate inflammatory response, trigger pulmonary fibrosis

53
Q

4 consequences of balance between viruses and interferons

A

host range barriers, therapeutics, vaccines, oncolytic vaccines

54
Q

consequence of using interferon as an antiviral treatment

A

associated with unpleasant side effects as activates many pro-inflammatory pathways

55
Q

describe use of interferon λ as an influenza therapeutic

A

signals to epithelial cells, which don’t recruit immune cells but simply cause neighbouring cells to enter anti-viral state (prevent cytokine storm)

56
Q

how are viruses deficient in control of interferons (either naturally or engineered) used in treatment

A

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)

57
Q

describe use of oncolytic viruses as cancer treatment

A

interferon deficient state of cancer cells, so kill cancer cells but not healthy cells

Y2 MCD Microbiology (9 decks)

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