Many inflammatory factors work in the innate response to cause inflammation; a process that leads to mechanisms which combine to stop or eliminate the offending pathogen. Some factors which work together during inflammation are called, as a group, the inflammasome. The inflammasome can help promote apoptosis in viral infected cells. Kaposi's sarcoma , a cancer which is often found in AIDs patients, is caused by a virus which has developed a way to survive the inflammasome and prevent apoptosis and survive inside cells.
1 Describe the components of the inflammasome.
2 Describe how the Kaposi virus causes cancer.
3 Describe how the Kaposi virus evades the inflammasome.
4 Inflammation causes a lot of illness in humans in our society today. In some cases inflammation can cause illness even without the presence of a pathogen. Is this evidence of bad design? Discuss.
Due October 16
1. The inflammasome is a protein complex that stimulates caspase-1 activation. This activation promotes the production of inflammatory cytokines interleukin-Ibeta and interleukin I8. It also promotes pyroptosis which is a form of cell death induced by invading pathogens. They contain a TLR receptor that attaches to incoming PAMP's, it then goes into a cascading effect of attachment proteins and phosphorylation of pathways. Inflammasomes can also be activated by an internal PRR's which can detect crystals, this is considered a second signal pathway where NLRP3 (receptor) binds with ASC and pro-capsase-1 to activate Capsase-I. Ultimately the two pathways intersect at the Capsase-I. When this happens the IL-Ibeta and IL-I8 serve the purpose of ultimately getting T-cells activated.
ReplyDeleteThe inflammasome is a highly complex molecule comprised of various proteins whose signal instigates an inflammatory response through cytokines and more specifically interleukin 1-beta. There is usually an adaptor protein ASC, a NALP 1 and two capsase proteins. These proteins allow the reactivity with Toll-like receptors which triggers the immune response. The capsase proteins work with pro- 1L-1 beta and pro-1L-18 which are phosphorylated and continues the cascade response. The unique aspect about the inflammasome is that it can be triggered by something other than a pathogen, like a crystal, anything else that is foreign to the body.
ReplyDeleteThe Kaposi virus is a virus that causes cancer of the blood vessels that occurs under the skin in the subcutaneous layers and mucus membranes, most commonly found in AIDS patients. Researchers have found that this virus derives a cytokine that represses the immune system. The viL-6 cytokine protects cells infected with this virus from undergoing cell growth arrest or apoptosis. viL-6 inhibits the signaling of antiviral factor interferon (IFN) which is what prohibits the continuous growth cells that are infected with a virus. The Kaposi virus has the ability to perceive the increase in the production of IFN and in turn increases the amount of viL-6 produced. The blocking of IFN allows the infected cells to continue to grow and proliferate at a high rate. This is the cancer. The Kaposi virus also can cause normal cells to grow at an alarming rate.
ReplyDeleteThe Kaposi virus evades the inflammasome by the use of the open reading frame 63(orf)which is a tegument protein which prohibits the activation of NLRs which is a specific class of Pattern Recognition Receptors (PRRs). The blocking of these receptors prevents the signal from going to the inflammasome and inducing an immune response. The Orf63 could be called a homolog of the NLR proteins in order to suppress the immune system.
The inflammasome consists of two pathways that come together to form the end result IL-1beta and IL-18. The first starts with TLR activation by PAMPs. It eventually gets to NFkB where it creates pro-IL-1beta and pro-IL-18. The second can be activated by crystals and causes the creation of caspase-1. Caspase-1 combines with pro-IL-1beta and pro-IL-18 to create the end result of the inflammasome which is sent out, IL-1beta and IL-18.
ReplyDeleteThe entire mechanism of how the Kaposi virus causes cancer is not known. What we do know is that the virus contains genetic material which it brings into the cell causing the cell to divide uncontrollably and invade neighboring tissues.
One way the virus evades the inflammasome is through the use of tegument proteins. Tegument proteins are a cluster of proteins that line the space between the envelope and nuclear capsid of all herpes viruses. They aid in viral DNA replication and immune system evasion. In Kaposi’s sarcoma herpes virus, the tegument protein ORF63 modulates the activation of the inflammasome response which inhibits the immune response against the virus. ORF63 most likely interferes with signaling.
No, I think inflammation without a pathogen still has a purpose. It alerts you to the fact that you are hurting and should possibly seek medical attention or an ice pack. It also helps heal the damaged tissues. Without inflammation, damaged tissues could not heal.
I agree with Shannon that the entire mechanism of how the Kaposi virus causes cancer is not known.The Kaposi virus can possibly cause a mutation in a cell by incorporating its genetic material, which can cause an alteration of the instructions that control cell growth, and as a result cause cancer. Cancer causes cells to divide and grow uncontrollably, forming malignant tumors and invade nearby parts of the body.
DeleteFurthermore, I also agree that "inflammation without a pathogen still has a purpose". I don't think its evidence of bad design, but perhaps inflammation without a pathogen is not only alerting the body of the presence of a pathogen; but also that the body is not functioning correctly somewhere. Without the presence of inflammation, wounds and infections will never heal.Inflammation allows both destruction and healing of the tissue from the inflammatory process.
An inflammasome is a complex of the innate immune system that comes together inside the cell and works with other pathways to produce interleukins. The first signal involves the TLR pathway. A ligand binds to a TLR receptor, which triggers association of MyD88 with the TIR domain, as well as the assembly of IRAK1/IRAK4 complex. IRAK4 phosphorylates IRAK1, which creates a binding site for TRAF1. The IRAK1-TRAF6 complex dissociates from IRAK4 and activates the protein kinase TAK1. TAK1 then phosphorylates IKK, which in turn phosphorylates IκB, causing it to release NRκB. NFκB then translocates from the cytoplasm of the cell to the nucleus where it works as a transcription activator for pro-IL-1β and pro-IL-18. This pathway is called the NFκB pathway. Pro-IL-1β and pro-IL-18 are both pro-interleukins. In order for these to become active interleukins, another pathway must be utilized. The inflammasome, which is often activated by crystals or other non-microbial elements, cleaves pro-caspase-1 to caspase-1. Caspase-1 then cleaves pro-IL-1βand pro-IL-18 to IL-1β and IL-18. These cytokines are then able to leave the cell and activate inflammatory processes as well as pyroptotic pathways. The inflammasome itself is made of NLRP (NOD-like receptor proteins) and ASC (an apoptosis-associated protein), which binds to pro-caspase-1 and cleaves it to caspase-1. NLRPs are internal PRRs (pathogen recognition receptors) that can recognize non-microbial elements such as crystals.
ReplyDeleteThe Kaposi’s sarcoma is a tumor caused by human herpesvirus 8 (HHV8), now known as Kaposi’s sarcoma-associated herpesvirus (KSHV). It is a systemic disease that can cause cutaneous lesions, and arises as a cancer of lymphatic endothelium that incorporates its genome into cellular genes that cause tumors. KSHV is a human tumor virus that steals many host genes that code for many proteins involved in the immune response and DNA synthesis. KSHV Orf63 is very similar to NLRP1. Orf63 is able to block immune responses that are dependent on NLRP1, meaning that the inflammasome will be blocked from properly working. If the inflammasome does not work, then pro-caspase-1 is not cleaved to caspase-1, and no interleukins are produced to activate the rest of the immune response. Once the virus has control of the cells, it causes the infected cells to replicate at an increased rate. A vastly increased rate of cell replication is the definition of cancer.
Even without the presence of a pathogen, the inflammasome is still important. The interleukins that the inflammasome helps produce are needed for other processes then just immune response. Research suggests that interleukin-1 is involved in the central nervous system, specifically memory function and long-term potentiation.
1. The inflammasome is an oligomer that consists of NLRP3, ASC, and pro-caspase 1. This component of the innate immune system is activated by either crystals or an efflux of K+. The presences of crystals (i.e. asbestos) causes’ lysosomal damage which in turn activates the inflammasome complex. When there is an increase in intracellular Sodium there is an efflux of Potassium in order to maintain cellular equilibrium. Once the inflammasome is activated by either of these signals, the pro-caspase 1 is cleaved and phosphorylated. This active Caspase 1 then cleaves pro-IL 1B and 18 into their active interluekens. IL1B exits the cell and induces fever. IL18 activates T cells. This results in an immune response.
ReplyDelete2. HIV is a virus that damages the immune system. That damage leads to full blown AIDS which can result in other types of infections such as KS. The risk of developing KS is linked to a lower CD4 count. The KSV or KSHV (KS herpes virus) is a large double stranded DNA virus with a capsid. The capsid is surrounded by a tegument, which is then enclosed in a lipid envelope. After infection the virus enters into the lymphocytes, where it remains in a latent state. In this state it expresses the viral-latency associated nuclear antigen (LANA). The virus exists as an episome (a naked circular piece of DNA) that is self replicating. LANA tethers the viral DNA to the cellular chromosomes. It then inhibits p53 and retinoblastoma proteins. This virus also suppresses viral genes that are needed for full virus production and assembly, known as lytic replication. The signal which triggers inflammatory responses provokes the virus to enter into lytic replication which occurs in the episome. This then leads to the formation of the linear DNA that is packaged into virus particles that exit the cell.
3. This virus encodes proteins that prevent inflammasome signaling. The KSHV tegument protein, Orf3, sequence shows a similarity to the NLR family. This protein directly interacts with NLRP1 which disrupts NLRPs association with ASC or pro-caspase1. Therefore, it results in the blocked ability of NLRP1 to associate with procaspase 1. This in turn, inhibits the activation of Caspase 1 and the cleavage and secretion of IL 18 and IL 1B.
ReplyDelete4. Inflammation apart from a pathogen is not a bad design feature because it can alert the body to heal tissue damage and signal the brain to compensate for pain or tissue damage. As a result of this, it can be a necessary design feature when there is an injury and tissue damage. In example, when someone sprains their ankle, there is a substantial amount of inflammation. This inflammation causes less mobility in the joint, which in turn gives the tissue time to heal. The inflammation also causes nutrients to be brought to the area of damage and increase the rate of healing.
2&3. The Kaposi virus is considered an oncovirus. THis specific virus falls into the category of "any virus with a DNA or RNA genome causing cancer and is synonymous with 'tumor virus' or 'cancer virus.'" Early on scientists began discovering specific herpesvirus-like structures in KS patients. When this virus enters the body, different signals, such as inflammation, may cause the virus to enter into lytic replication. This replication causes the viral episome (a circular piece of DNA) starts replicating itself in the form of linear DNA molecules that are packaged into virus particles which are expelled from the cell, to infect new cells or to be sent to a new host. When the virus enters into lytic replication, "thousands of virus particles can be made from a single cell, which usually results in death of the infected cell, hence the term lytic replication." This is where this virus is given the name of the oncovirus because it is a mass destruction of cells. Kaposi's sarcoma develops when someone who has been infected with the virus (KSHV) is immunocompromised due to AIDS or even certain medical treatments. According to Science Daily Website, "Kaposi sarcoma virus has a decoy protein that impedes a key molecule involved in the human immune response." KSHV ORF63 (decoy protein) interacts with NLRP1, NLPR3 and NOD2 (all NOD-like receptors) and inhibits IL-1β production during the viral life cycle by preventing NLRP1 oligomerization, which is the activation confirmation of the Inflammasome.
ReplyDelete4. I do not think that the inflammatory response without a pathogen reflects a bad design. Our body is still alerting us, and producing good things that can heal tissues and a damaged area. Such as WBC's, macrophages, etc. These are only activated by an "inflammatory" response.
(1)Inflammasome consist of caspase 1, caspase 5, PYCARD, and NALP. However the exact composition of an inflammasome depends on the activator which initiates inflammasome. The role of both caspase 5 and caspase 1 is an enzyme that proteolytically cleaves other proteins into active mature peptides. NALP is a NOD-like receptor that detects conserved pathogen characteristics. The NOD-like receptors are part of PRRs. The PRRs consisted in inflammasome are TLRs, RLRs, NLRs, and ALRs. All these receptors play a role in initiating immediate defense mechanisms and orchestrate adaptive immunity. Lastly, PYCARD is a gene that encodes a apoptosis-associated protein.
ReplyDelete(3)Karposi virus evade the inflammasome by the use of the ORF63 tegument protein. This protein prohibits the activation of NLRP1, NLPR3 and NOD2, examples of PRRs. When the ORF63 prohibits the PRRs, this inhibits signaling of the inflammasome. The PRRs are the components of the inflammasome that enables immediate defense mechanisms and orchestrates adaptive immunity.
1. The inflammasome consists of many various factors and elements required for a cell to be able to detect the presence of a pathogen infection. The essential components of caspase 1, PYCARD, NALP, and caspase 5 are all involved in various steps of the pathway toward cellular self-destruction in the face of viral takeover.
ReplyDeleteCaspase 1 is the main protein involved in turning a cellular signal into the actual development of an intercellular response. PYCARD and NALP are assistant proteins that help with the processing and interactions of the various cell-signaling molecules. Caspase 1 is alerted primarily by the NLR-receptors found in the cellular membrane. These are the first proteins to interact with an incoming virus. These Noll-like receptors start a cascade mediated by caspase 1, first by activating the inactive form of caspase 1, and then standing by while caspase 1 goes on to promote various genes in the nucleus involved with pyropoptosis.
2. The Kaposi virus is a deadly pathogen that infects human cells in a very tricky and devious manner, bypassing many of the usual cellular protection mechanisms in order to achieve a great chance of take over. The way that Kaposi turns perfectly normal human cells into cancerous "rogue" tissues is understood through realizing that the Kaposi virus contains in its genetic material many eukaryotic genes and proteins. These genes activate eukaryotic-type pathways independently of normal cellular processes, and so develop an additional subset of intercellular development completely independent of how a normal cell is to grow and behave. When this virus is activated, it causes mayhem using the host cell's replication machinery, and in an attempt to produce more copies of the infectious viral agent, ends up creating a non-responsive growth cell that no longer obeys the parameters set up in a tissue organism. This is what forms the basis of tumor tissue.
3. The Kaposi virus manages to keep a cell alive by evading the inflammasome response. If it were unable to do this, any cell infected with the virus would destroy itself and cause phagocytosis of the viral material. However, the Kaposi virus is able to shut down the inflammasome cascade response using the eukaryotic type protein products in its own genome, and then inserts its own genetic code into the host cell's nucleus. This allows the virus to remain undetected in a cell, as it is essentially disguised to look exactly like additional cellular code. The virus will remain "latent" and undetectable for several replication generations, thus proliferating throughout a cellular tissue set without being caught and eliminated by the immune system.
4. Inflammation, with its various negative side effects, is still a necessary and entirely well-designed protective system. Hyper-sensitivity is one of the most common problems people face when their immune system "acts up". However, this over-protectiveness helps to serve a greater overall purpose. A hyper-sensitivity like allergies points to a very redundant system that needs to be maintained at all times. The immune system is automatically kept up to date and maintained throughout an organism's lifetime, however, without continual subtle immune system responses over an organism's lifetime, various attributes and responsiveness factors can be lost over time due to the limited lifespan of immune-related cells. Even an over-sensitivity to various non-pathogenic substances help to keep our immunity system "at the ready" at all times and highly responsive when there is a very real threat to our body.
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ReplyDelete1)Inflammasomes consist of several different subunits. The main components are caspase 1,PYCARD(which in turn is made up of ASC),Nod-like receptors,and in some cases caspase 5. The exact structure of the inflammasome is defined by the substance that triggered the activation of the inflammasome in the first place.
ReplyDelete2)Like other tumor viruses, the Kaposi Sarcoma Herpes Virus causes cancer by attacking various tumor suppressor pathways.The virus infects lymphocytes where it then attaches itself to chromosomes and disables genes for tumor suppressor proteins such as p53 and retinoblastoma protein. The virus then uses the cell machinery to replicate its own DNA, lyses the cell and releases many more virus particles into the system. Generally this virus is easily dealt with by the immune system, but patients with highly compromised immune systems (like those who have AIDS) have no way of fighting the virus off. The virus replicates itself and inhibits more and more tumor suppressor genes. This causes cancerous tumors to grow all over the body.
3)KSHV and many other viruses evade inflammasome response by disguising themselves. KSHV expresses an NLRP1 homologue called Orf63. The body thinks that Orf63 is a NLR, but in reality Orf interferes with assembly of NLRP1. Without NLRP1, the inflammasome cannot function. Studies showed that Orf63 also decreases secretion of IL1 beta. Creepy.
4) I agree with Richard. The very fact that inflammation is a threat shows how well it is designed. You could say that it works too well. If you have a nuclear bomb, and you accidentally blow yourself up with it, the fault does not lie with the nuclear bomb, but the system that controls the bomb's detonation. Inflammation has a series of checkpoints that turn it off, but if even one of those is taken away, everything can go haywire. That shows just how effective inflammation is at fighting diseases. If inflammation wasn't so hard to stop, there would be more viruses like KSHV that fool it. KSHV is one of the only viruses that can bypass inflammation, and it is only dangerous in immunodeficient patients. I don't know about everyone else, but I'm pretty happy with that design.
ReplyDelete1. Inflammasome is a molecule made up of proteins which stimulates pro-inflammatory cytokines (interleukin 1beta, and interleukin 18), when it is triggered by stresses or infection. IL-1B and IL-18 cause many different biological effects within the body when activated, like generating a fever or gathering leukocytes to the site of attention. Inflammasomes are composed mainly of caspase 1, PYCARD, NALP and they interact with toll-like receptors to mediate the appropriate responses to pathogens and other foreign things. There are multiple structures that the inflammsomes may take (NLPR1, NLRC4, NLPR3, etc), and each organization of the structure depends on the PAMP or foreign substance that activated it.
ReplyDelete