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Intrinsic cellular defense systems
systems that act rapidly within minutes of the initial infection of a cell and locally, within the infected cell or in nearby cells
- three stages of it
- 1) pathogen recognition
- 2) signal amplification
- 3) pathogen control
Once these proteins detect the presence of a pathogen, they set off a highly coordinated response that involves receptor-mediated signaling, activation of gene transcription, secretion of proteins, and cell-to-cell communication
This response leads to the secretion of cytokines, including interferons, and the activation of enzyme systems that inhibit replication of the infecting pathogen within cells
What are defenses outside of the cell
- innate immunity
- adaptive immunity
takes days to weeks to deploy its maximum effects.
However, what is beneficial about it is that, once you get exposed to it once, the second time, the response is much quicker. This is due tot he formation of memory cells
receptors located either on the cell surface or in endosomal membranes
recognize a variety of conserved molecular structures typically found in pathogens (ex: dsRNA)
What are defenses inside of the cell?
Prokaryotes and eukaryotes have different defenses
What are the defenses of bacteria?
- restriction enzymes
- CRISPR bacterial immunity
Explain restriction enzymes
- cuts specific sites on DNA
- can be used for cloning and other apps
- early form of innate immunity in pro-k cells, which have modifications on their own DNA to prevent degradation
- innate and unchanging
- kind of like adaptive immunity
- With this, bacteria can incorporate foreign DNA and recognize it as foreign when it encounters it again
Steps for CRISPR recognition
Phage infects bacteria
Bacteria cut up the viral DNA nand put it in specific places
The cells make a complex of proteisn (revolve around CAS proteins) with the foreign RNAs
Bacteria use this to recognize the foreign DNA upon further infection to degrade it
What can our cells do when they are infected?
- Starting as early as binding of a virus to a receptor, several alarms go off.
- When certain molecules that our body recognizes as viral bind to the molecules, our cells know that something is wrong. Therefore, they send out molecules
What are the molecules that are sent out?
- Interleukin-1a: molecular alarm
- Interferon: virus gets into the cell and triggers interferon expression--interferes with successful replication of virus in cell and nearby cells
- TLRs get released to recognize broad groups of molecules that we don't make but pathogens do
How do TLRs exist?
They exist in homodimers and are in various places of the cell
What does the cell usually do to damaged pieces of the cell?
it usually recycles it and releases the building blocks for reuse
In times of stress, what can happen?
The cells turn up the digestion and freedom of building blocks. An infection would also turn up the rate of self-digestion. This occurs in special compartments, known as phagosomes. It will digest the stuff in hopes of freeing up viral material for TLRs to recognize
plays a role in recognition of viral nucleic acids by TLRs
intrinsic cell process
involves the use of phagosomes
Aside from TLRs, what are other recognition proteins?
There is RIG-I and also MDA5. They recognize viral RNAs (ds)
Briefly explain the virus mediated signal transduction process that occurs?
Binding of viral proteins or nucleic acids to toll-like receptors leads to the recruitment of the downstream adaptor molecules MyD88 and TRIF
Most TLRs interact with MyD88
Through a series of reactions, these adaptors recruit protein kinases, which initiate the NF-kappaB signal transduction cascade
NF-kB moves into the nucleus and acts as a TF to induce expression of interferons, other cytokines, and interferon-stimulated genes
What is a host cell response to viral infection?
Cell can commit suicide as a result of infection. A lot of the signals inside and outside of the cell lead to apoptosis.
What are the two pathways of apoptosis?
intrinsic: internal stress/ viral DNA replication and DNA damage can cause the pathway to be activated
extrinsic: cells know that the cell is defective. It will signal it with a bunch of molecules, such as TNF (tumor necrosis factor). The cell notices a cell is infected, releases TNF, and causes apoptosis/ binding of a molecule to receptors on cell surface
Recognition of viral infection can trigger __, which involves the activation of __ and is triggered by infection.
Cellular recognition of virus infection leads to the production of __.
They are a hallmark of both the __ and __. And they mediate communication between the __ and __.
- intrinsic cellular defense system
- innate immune response
- adaptive immune system
Explain the cytokines.
- interferons: major players in host defense against most viruses; can be produced by either immune cells or normal cells
- Pro-inflammatory cytokines: activate immune cells in the circ system; can keep a pathogen localized in the inflamed area
- chemokines: recruit other immune cells to site of infection
- anti-inflammatory cytokines: suppress the pro-inflame cytokines; work to keep swelling at a level that won't cause damage
Things that the cell releases when infected to help stop the infection
The virus gets in, sets up shop, makes viral proteins. The cell responds by making viral interferons since viral infection induces its expression. The cell itself may die but it will signal other cells by sending interferons to protect the cell.
What happens when cells receive the interferons?
- If a cell is being hit with it, it will make 2',5'-oligo(A) synthetase and ribonuclease L.
- The 2',5'-oligo(A) synthetase is activated by binding to dsRNA and then makes an oligo(A) that activates ribonuclease L to degrade both host and viral mRNAs, stopping the infection
What is the mechanism of antiviral activity directed by?
Expression is increased by presence of virus. It is activated by dsRNA. Two molecules bidn to the RNA, phosphorylating each other and inducing a conformational change that increases their kinase activity. They then phosphorylate a variety of cellular proteins.
Explain PKR in relation to eIF-2
- 1) eIF-2 is phosphorylated by PKR, which leads to formation of an inactive complex that involves eIF-2 bound to guanosine diphosphate and the recycling factor eIF-2B. Normally, eIF-2B catalyzes the exchange of GDP to GTP, and the regenerated eIF-2-GTP complex binds to initiator met-tRNA and forms a translation initiation complex with mRNA and a ribosomal subunit.
- 2) Since the GDP-GTP exchange reaction is blocked, insufficient met-tRNA-eIF-2-GTP complex is formed and translation initiation can't occur
Almost all viruses..
have at least one mechanism for averting these processes of infection. They can prevent interferon inhibition. Some hide their RNA so as not to be found. Others inhibt TLR synthesis and RNA helicase signaling. Others inhibit functioning of IRF-3 and activation of PKR