Magor- Topic 7: Immune defenses against viruses Flashcards
Innate immunity can mean difference between life & death. Because
Because the adaptive immune system takes 3 days to get up and running & that’s so much time & during that time, it determines whether you live or die from a viral infection.
Advantage of adaptive immune response
You have a memory of that infection
When does the adaptive immune system & recovery begin?
If it gets through a round of replication, there’s usually some symptoms & disease associated and then it will be the beginning of adaptive immune system & recovery.
Very early, the production of _______ and _______ are critically important in the immune response
interferons (IFN) and cytokines
You need a lot of interferons in innate immune response. But what happens if you get a lot of cytokines?
That’s a bad thing
Viruses have lots of ways of turning down interferon & turning on pro-inflammatory cytokines, which doe snot have a good outcome.
Virus titre decreases as
As the cytotoxic T cells arise
These two are tissue residents. So they are the first cells to see the viral infection in innate immune response
Macrophages and Dendritic cell
These cells are the early responders in innate immunity
Natural killer cell
Main antiviral players in adaptive immunity
B cell (make antibodies)
T cell ( make cytotoxic T cells)
_______ will become some of those first responders in innate immune response. They are 70% of our WBCs & they come in quickly post-infection.
Neutrophil
Innate defenses are most important in _____ infection
acute
Pattern recognition: Antigens are recognized by _____________
innate immune system
- this is gene encoded
Innate immune system is responsible for recognizing that something poses _________
danger
Antiviral pattern recognition receptors are _________ or ________
endosomal or cytoplasmic
Three toll receptors that are important in viral infections
these are the endosome receptors
TLR3, TLR7, TLR9
They’re the ones that actually detect pathogens in the endosome.
Because many viruses come in through that receptor mediated endocytosis, they are in the endosome.
What does TLR3 detect?
dsRNa
What does TLR7/8 detect?
ssRNA
What does the TLR9 detect?
unmethylated CpG DNA
What is the final step after the detection of TLR3,7,9?
It is turning on pro-inflammatory cytokines in the help of IL-6 and INF
Two important cytoplasmic receptors
These two detect RNA
Any virus that is making RNA in the cytoplasm is going to get detected by these receptors.
MD5 and RIG1
MDA5
- cytoplasmic receptor
- detects long dsDNA
- particularly detects Vpg on the genome & signals through, turns on IFN & pro-inflammatory cytokines
RIG1 is a cytoplasmic receptor that detects _______
short dsDNA (esp. hairpins)
cGAS
- cytoplasmic receptor that detects DNA
- works through sting to turn on IFN
Neutrophils
- filled with granules that dump out defensins that are antiviral
- phagocytic
- first to arrive at sites of infection
- The neutrophils come in in response to signals sent out by dendritic cells & macrophages
- About 70% of the circulating leukocytes are neutrophils
- Granules contain antimicrobial peptides including defensins
Macrophages release cytokines that act locally (recruit more leukocytes) and systematically (many effects)
What are three pro-inflammatory cytokines?
IL-1
IL-6
TNF-alpha
Systemic effects of pro-inflammatory cytokines
- cause fever
- cause you to go to sleep
- make you feel tired
- pro-inflammatory cytokines act on hypothalamus
- colony stimulating factors act on bone marrow to increase WBC output
It’s always not a good idea to take drugs to make fever go down, even though you feel like crap, it is serving purpose
the most potent antiviral thing known & it is the thing that makes you feel like crap when you’re sick.
Interferon (IFN)
Acute phase proteins
- are made by the liver 100-1000 fold upregulation
- called acute phase proteins because during the acute phase of an infection, they’re elevated sometimes.
Proinflammatory cytokines induce liver to produce ___________
acute phase reactants -effector proteins made in response to infection.
-often bind directly to virus
-act as opsonins facilitating phagocytosis
C-reactive protein
can be used as a diagnostic for infection
Mannan-binding lectin (MBL)
- binds to mannose on viral glycoproteins and acts as an opsonin facilitating phagocytosis
- can also activate complement via the lectin pathway
αGal
- on many viruses that are made in non-primate hosts
- sugar that’s on the surface of glycoproteins
- we don’t make αGal because there’s been a mutation in the enzyme
- all other non-primate animals make αGal
- main line of defense against animal viruses is due to antibodies against αGal and complement activation
What is one of the reason why you don’t really have to worry about getting a virus form a cat or dog?
You make an immune response to this αGal
What are the the Type I interferons
IFN-α and IFN-β
This is a Type II interferon
IFN-γ
IFN-α
- produced by: leukocytes (WBCs)
- turned on by: virus infection, dsRNA
IFN-β
- produced by: fibroblasts, epithelial cells
- turned on by: virus infection, dsRNA
- made by all cells
IFN-γ
- produced by: T cells, NK cells
- turned on by: antigens, mitogens, IL-2, IL-12
Mitogens
non-specific stimulators of lymphocytes
The innate immune response is amplified by
cooperation in the immune system
Activated macrophages -> make TNF-alpha
TNF-alpha -> activate NK cells
NK cells -> activate IFN-γ
IFN-γ -> activate macrophage
Interferon (IFN)
- effectors made by cells
- “warning protein” made by leukocytes (especially dendritic cells) if they detect virus
The IFN-α and IFN-β that are made by infected cells are detected by neighboring cells using the IFN receptors. What does this do?
It turns on about 300 genes we call IFN stimulating genes
Type I Interferons (IFN-α and IFN-β ) local effects on other immune cells
- induce resistance to viral replication in all cells
- increase MHC class I expression and antigen presentation in all cells
- activate NK cells to kill virus-infected cells
‘Antiviral state’
- turned on by Type I interferons
- those cells become resistant to infection, which helps to contain the infection as well
eg. TRIM22 inhibits trafficking of HIV gag proteins
All cells can make IFNs but those ________ dendritic cells make lots of IFNs than any other cell type
specialized
2’-5’ oligoadenylate synthetase (OAS)
- is activated to make oligoadenylate (AAAAAAA) which in turn activates RNase L
- takes adenylase & makes a chain of them
RNase L
- degrades cellular and viral mRNA in that neighboring cell, suppressing infection
dsRNA activated protein kinase (Pkr)
- stops new protein synthesis
Defense against intracellular pathogens by cytotoxic T lymphocytes
- Cytotoxic T cell kill virally infected cells
- The T cell will actually contact the virally infected cell & deliver a signal to kill that cell
Cytotoxic T cells kill ______________, by killing the infected cell
intracellular pathogens
The key point to understand some of the antiviral mechanisms
- CTLs recognize viral peptides presented on MHC class I
- IN a normal cell, proteins are getting chopped up, put on MHC class I and they go into the surface
- When that cell gets infected by a virus, the viral protein will get presented on the outside of that cell & those viral proteins are seen by cytotoxic T cells
- The key point here is these peptides are coming from newly synthesized proteins
CTL kill by __________
apoptosis (forced cell suicide)
-clean cell death
The activation of cytotoxic T cells requires three steps
- cytotoxic T cells will go through many rounds of proliferation & differentiation if they get this T cell help
- The initial activation of cytotoxic T cells involves an APC, because in order to prime naive CD8 T cell, you need both presentation of a peptide on an antigen presenting cell to T cell and you need the 2nd signal (co-stimulating signal)
- Antigen stimulated CTL are activated to divide 7-10 times and differentiate into effector and memory T cells
IL-2
T helper cells will make that IL-2 that is needed for proliferation of the cytotoxic T cells
CTL effectors live for _________ while memory cells live for ________
CTL effectors live about a week
Memory cells live for many years and are present if virus re-infects
Memory cells are made only if
CTL is primed by IL-2 from a T helper.
Very young & very old age are ______(more/less) susceptible to disease from viruses
more
Cytotoxic T cells (serial killers) kill only targets bearing _______________
specific non-self antigen
viral antigens are expressed on infected cells
Does a CTL get damaged in the killing process?
No, it can kill and kill
Natural killer (NK) cells
- look just like T cells
- are also cytotoxic lymphocytes
- play a critical role in the early innate response to viruses
- have the same lytic molecules as CTL
what inhibits NK killing?
Engagement of MHC class I by NK inhibitory receptor inhibits killing
What activates NK killing?
Down regulated MHC class I results in activation of NK killing
Viruses often down-regulate surface expression of MHC. This makes them a target of NK cells
