Leslie's "Internal affairs" 2010

From Biol557

• Subtitle: "Newly discovered cytoplasmic defenses sound the alarm when pathogens penetrate our cells."
• Inside the cell is a great place for a pathogen because it can steal resources, gain access to machinery, and evade the immune system.
  • Hence some of the biggest pathogens live inside our cells, including the infectious agents of AIDS, tuberculosis, and malaria.
• There are cellular mechanisms that try to keep pathogens out of cells, but there are also more subtle systems that warn the body of infection and try to maintain the sanctity of the cytoplasm.
• Cells lay out traps that get tripped by pathogens when they enter the cell. This causes the signaling for inflammation or even cellular self destruction and a warning to surrounding cells.
• These mechanisms, when faulty, are the cause for several diseases including gout and Crohn disease and our reaction to asbestos.
• Understanding these mechanisms may lead to better manipulation when trying to treat disease or induce an immune response when administering a vaccine.

[edit] Looking inward

• Many animal cells, including dendritic cells and macrophages have Toll-like receptors that recognize pathogen-associated molecular patterns (PAMPs) such that when they bind they signal to unleash the innate immune response and the adaptive immune response.
• Having found "R" proteins in plants that detect pathogens, researchers looked for homologous proteins in mammals and found plenty. We call these nucleotide-binding domain and leucine-rich repeat containing proteins (NLRs).
• NLRs distinguish bacteria, parasites, and other interlopers.
• Some of these pathogen detecting proteins in mammals contain RIG-I-like receptors which check for the genetic material of viruses.
• There are also proteins like AIM2 and DAI which check for the DNA of bad guys.
• Now that we know about these proteins, we have the tools to investigate how they work.
• Some of these intracellular proteins work much like Toll-like Receptors (TLRs) in that they detect PAMPs. Others, like Rig-I, detect RNA molecules that identify viruses.
• RNA polymerase does its thing in the nucleus, but in the cytoplasm, RNA polymerase will copy any DNA if finds, thus making it double stranded which is recognizable by RIG-I. Thus, RNA polymerase helps the RIG-I pathway see more material and therefore increases its chances of finding evidence of an invader.
• Still, some of these proteins are a mystery as to how they detect things as foreign, like NLRP3 which detects everything from asbestos and monosodium urate (gout) to bacterial cell wall.
  • It is suggested that there may be separate detecting molecules for each pathogen.
  • It could also be that cellular damage or signals from cellular damage caused by the intruder is what is detected, not actually any foreign material. This would explain how one protein NLRP could be reactive to such a wide variety of agents.

[edit] Gotch--now what?

• Once an intruder is recognized some cells can go through "autophagy", a type of self eating of their own cytoplasm, thus destroying the interloper.
• A cell can form a complex of proteins called the inflammasome which seems to be crucial to immune response since mice without them die from otherwise easily beaten vaccinations.
  • "The activated sensor draws in more NLRP3 molecules and other kinds of proteins to form an inflammasome (2). After the enzyme caspase-1 (purple) switches on, it activates the cytokines IL-1 and IL-18 (3). The end result is the release of these inflammation-promoting molecules (4)."
• Multiple steps for generating inflammation makes sense because, while it is important for fighting infection, it is also a major cause of disease including heart disease, Alzheimer disease, and cancer.
• And if the cell cannot clear the pathogen, it dies, but not just any death: "But when certain NLRs detect intracellular invaders, they switch on caspase-1 in a manner that instigates the cell death program and the production of IL-1 and IL- 18. Cookson and his then–grad student Molly Bergman dubbed this process pyroptosis: essentially, a fiery death. Not only does a pyroptotic cell pour out cytokines that spur inflammation and fever, but it also spills its insides, which also rouse the immune system."

[edit] Cheaters do prosper

• There are examples of viruses and other pathogens that fight the signals sent out upon detection.
• There are examples of pathogens that try to inhibit inflammation after they have been detected.
• There is a set of very rare disease that cause people to execute inflammation after being exposed to cold temperatures for just a few minutes. Realizing this was an inflammation issue, researchers repurposed an IL8 inhibitor as a drug to inhibit the inflammatory response for these patients.
• People with Crohn disease could also benefit as it is an inflammatory disease.
• We may get better vaccines out of this too, because we think that alum (the only adjuvant approved in the US) works by provoking the inflammasome and thus generating a better immune response. If so, we may be able to fine tune this to generate an even better response to vaccinations.
• It's an intracellular, molecular arms race and the faster evolvers (the microbes) will always win.