week 6 Flashcards
first line of defence
passive barriers such as skin, mucous. membranes, lysozymes, gastric juice and normal body flora. part of innate immunity
second line of defence
also part of innate defence but needs to be activated. effective in less than 24 hours. natural killer cells, eosinophils, cytokines and fever. often activated by signalling molecules
third line of defence
complex activation, requires cell proliferation and effective after a few days. needs to produce antibodues. t and b cells
toll like receptors
a supbyte of pattern recognition receptors (PPR) receptors that recognize pathogen associated molecular patterns (PAMPs). there are different subtypes that recognizes different things. for example TLR3 recognizes double stranded RNA. they are located at different locations in the cell. some are found on the plasma membrane and some in the endosome for example. when they bind to a ligand they dimerize and assemble with adaptor molecules such as MYD88 and TRIF. MYD88 will activte nfkappab and IRF7 and TRIF activates IRF3. these are transcription factors and MAP kinases that leads to transvription of interferon type 1 and proinflammatory cytokines that plays an important role in the cells antiviral defence. this also helps in initiation of adaptive immune response by presenting viral antigens to b and t cells
rna helicases
recognizes viral rna in the cytoplasm and initiates a downstream signalling pathway. two common rna helicases are RIG-I and MDA5. upon interaction with viral rna they dimeriza and interaction with adaptor protein MAVS located on the mithocondrial membrane. the interaction is facilitated by CARD domains found on RIG-I that are exposed when binding viral rna due to a conformational change that allows binding to MAVS. this stimulates the activation of transcription factors IRF3/7 and nfkappab leading to transcription of interferons and pro-inflammatory cytokines. IRF-3 leads to the transciption of type 1 interferon and nfkappab to transcription of pro-inflammatory cytokines
cGAS/ STING pathway to recognize viral DNA
cGAS is a host protein that recognizes foreign dna in the cytoplasm and generates cGAMP that binds to STING in the ER. this in turn activates TBK1, IRF3 and NFkappaB to produce interferons and cytokines. there are many receptors reacting to dna in the cytoplasm since this is foreign to our cells and some can also induce apoptosis. there is also some evidence suggesting that cGAMP is released from cells and can induce an antiviral state in neighbouring cells upon activation of the cGAS pathway
interferons
interferons are cytokines with important regulatory functions in the innate and adaptive immune system. they bind to receptors and cause activation of signalling pathways resulting in alteration of gene expression. they initially function locally to bind to neighbouring cells but in larger quantities they can be released into circulation and have global effects such as symptoms of sickness.
interferon-induced jak-stat pathway
interferon type 1 binds to a cell surface receptor, causing the receptor to dimerize. this brings the receptor-associated JAKs in close proximity and they then phosporylate each other which activates their kinase activity. they then phosphorylates the receptor, creating binding sites for SH2-domains which causes STAT1 and 2 to bind. the STATs are then also phosphorylated and dissociate from the receptor and dimerize (1 and 2 bind together). they can then enter the nucleus and induce transcription of target genes.
interferon stimulated genes (ISGs)
these are antiviral genes and we have about 2000 of these genes. for one infection, the body typically produces about 200 ISGs.
MxA protein
an interferon stimulated genes which forms oligomers to trap viral components in the cytoplasm of cells and prevents them from forming viral particles. is used widely as a marker of infection. very potent against influenza
OAS and RNaseL
presence of dsDNA in the cytoplasm activates OAS enzymes which catalyzes the formation of a nucleotide called 2-5A. two 2-5A then binds to and activates RNaseL which is an endoribonuclease that cleaces RNA molecules from both the host and virus to stop virus maturation and spread in the body. excessive RNaseL acitivity can lead to apoptosis. production of RNaseL and OAS is induced by interferons but small amounts are always present in the cell and is part of the innate immune system.
protein kinase R (PKR)
the inactive PKR monomer contains a dsRNA binding domain. when it binds dsRNA it is phosphorylated and dimerizes which activates it. the activated PKR then phosphorylates the transcription factir EIF2a which stops all host cell translation and thereby virus protein translation.
virus countermeasures-TLRs
viruses can block TLR signalling to evade the immune system. they can do this in multiple ways, for example by inhibiting expression of TLrs on the cell surface which makes it harder for the immune system to detect the virus. they can also interfere with the activation of TLRs by blocking the binding of PAMPs or modulate the signalling pathway. they can also target and degrade signaling or adaptor molecules in the signaling cascade. some of the big modulators of the tlr sognalling pathway are HCV and pox. pox blocks adaptor molecules by cleavege
virus countermeasures- RNA recognition
every step of RNA recognition can be blocked by different viruses. they can interfere with the recognition process, helicase activation, MAVS signalling or prevent the activation of trancription factors
virus countermeasures- inhibition of IFN signalling
block the jak-stat pathway in different ways. west nile virus prevents phosphorylation, SARS CoV-2, measles and mumps prevents niclear import of STAT
