Lecture 6 Flashcards
What are the 2 categories of virulence factors?
- factors that promote bacterial colonization of the host
2. factors that damage the host.
What does virulence factors 1 have the ability to do?
- The ability to produce cell wall components (pathogen-associated molecular patterns or PAMPS) that bind to host cells causing them to synthesize and secrete inflammatory cytokines and chemokines
- The ability to produce harmful exotoxins
- The ability to induce autoimmune responses
What do PAMPs do?
PAMPS recognition promotes host cells to synthesize and secrete inflammatory cytokines and chemokines
What does activation of the complement pathway lead to?
Activation of the complement pathways leads to more inflammation, opsonization of bacteria, and chemotaxis of phagocytes
What does activation of the coagulation pathway lead to?
Activation of coagulation pathway lead to the clotting of blood to stop bleeding, more inflammation, and localization of infection
What is the purpose of isle 10?
Inflammatory response needs to be mediated at an appropriate level…the body has mechanism to mediate this such as aisle 10 (an anti-inflammatory cytokine)
What is the structure of Toll-like receptors?
Single transmembrane protein with a TIR (Toll isle 1 Receptor domain) domain in the inside of the cell. On the other side of the of the domain you have leucine rich repeats called LRR
What are the different TLRs and what do they recognize?
TLR4 - activated and recognized LPS
TLR3 - RECOGNIZE DOUBLE STRANDED RNA of a virus
TLR 7/8 - recognize and get activated by anti-viral compounds
TLR2 - shorthand designation for things such as phosphotidylglycans, glycerophosphoinositol
What is NF-kB?
NF-kB is a heterodimeric transcription factor from the rel-A family of transcription factors, and is made up of two subunits named p50 and p65.
Other members include c-rel, RelB, p52, as well as the two precursors p105 and p100.
Multiple subunits all interact to form a variety of factors with different apparent functions.
What are the importance of NF-kB?
Proinflammatory response: a first line of defense against infectious diseases and cellular stress
Signal Activated NF-κB: immune defense (Immune response, inflammatory response, acute phase response)
Anti-apoptotic function: Persistent activation in many cancers
Cellular growth
Activated NF-κB: enhanced cyclin D expression; growth
What is the role of Ik-B?
NF-κB/Rel proteins are homo- and hetero-dimeric TFs that in resting cells are retained in the cytoplasm in complex with IκB.
Upon stimulation, IκB is released from the complex, allowing NF-κB to rapidly translocate to the nucleus where it binds κB-sites and activates target genes.
IkB blocks the nuclear signal region for p.65 nucleus by binding to NFKb complex, keeping the complex inactive in and retained in the cytoplasm
Why is dimer formation important in NFk-B?
Dimer formation is important because of NFkB ability to bind regulatory DNA regions once in the nucleus…thus it has a large number of target genes
What dictates the combination of NFk-B heterodimers?
Preference for κB binding sites
Kinetics of nuclear translocation
Abundance in different cells
Describe the NF-kB scheme.
- When you have an infection, IKK phosphorylates Ikb, and it releases p55/60 diagram of NFkB.
- The nuclear complex becomes exposed and phosphorylated in the cell which causes it to
- form a dimer, thus it can be translocated into the nucleus where it can go and bind into the regulatory sites of the genes it want to activate.
- IkB then gets ubquinated, and degraded and released into the cell
Describe the TLR4 and LPS binding receptor?
- LPS bound by LPP that is circulating in body fluids
- LPP binds then to CD14 receptor on the surface of the cell…transferring the LPS to Cd14
- Cd14 get activated and binds to TLR4 and activates TLR4
- TLR4 then activated NF-Kb which goes and induces a number of genes
- Too much of this can be bad and damage the host tissue
Describe endotoxin shock due to defects in LPS recognition.
High doses of LPS given to mice will cause an endotoxic shock
Mice w/o TLR4 (LPS can’t activate the cells), the mice survive
You can also have mice that are depleted in MyD88. MyD88 is an adaptor protein that responses to TLR4 inside the cell and transmits the signal down to the NF-Kb.
What is System inflammatory response syndrome?
Cytokines causes damage at very high levels b/c of over activation of coagulation and complement pathway, and over activation of proteoglycans or leukotrienes causing damage to blood vessels and epithelium
Describe capillary damage during SIRs?
- With the production of large amounts of proinflammatory cytokines, neutrophils adhere to capillary walls in massive amounts.
- Chemokines cause neutrophils to release proteases and toxic oxygen radicals, the same chemicals they use to kill microbes, and
- the neutrophils have adhered to it during diapedesis resulting in damage to the capillary walls and leakage of blood.
What are the mechanism in DIC?
Prolonged vasodilation and increased capillary permeability:
- Plasma leaves the bloodstream and enter the tissue.
- hypotension and hypovolemia
Activation of the blood coagulation pathway and concurrent down-regulation of anticoagulation
- clots form within the blood vessels throughout the body (disseminated intravascular coagulation (DIC)
- Further drop in blood and oxygen supply through tissues and organs
