IFN pathway produces interferons but also inhibits the production of KC and Mip2

IFN pathway produces interferons but also inhibits the production of KC and Mip2

ResearchBlogging.orgThe H1N1 flu has now been circulating for over 3 months and has landed on every continent (Antarctica doesn’t count as a continent in the medical world), infecting thousands of people. People continue to die at a steady pace and yesterday a girl in Brazil died with atypical symptoms (yes it is in Portuguese, but I’ll summarize what it says here).

This girl had contracted a pneumococcus infection and ended up dying from septicemia.  The physicians speculate that her contraction of H1N1 may have lowered her immunity to a pneumonia infection, leaving her vulnerable to the bacteria.

Although the science is still out on this issue there is a model that has been presented about why those infected with influenza are at an increased risk for secondary pneumococcus infections.  An article in the Journal of Clinical Investigation seems to pinpoint the reason for the increased risk of secondary infection.

The scientists proposed that when the body responds to a viral infection there is a concurrent loss in the ability to respond to bacterial infections.  Type I IFN receptors were targeted because they are a large part of the innate response to viral infections.  When activated they produce a cascade of cytokines that act to inhibit viral replication.  This is the early response the body takes as it goes through the process of antibody production and maturation (maybe one of the most fascinating subjects in immunology).  The researchers found that when mice had their Type I IFN receptors knocked out there was a much higher level of KC and Mip2, two chemoattractants used to recruit neutrophils to the site of bacterial infection.

So it looks as though the Type I IFN receptors inhibit the production of KC and Mip2.  This would cause far less neutrophils to be found at infection sites in mice responding to an influenza challenge, which is what the researchers saw.

This is another key in developing a model of how one branch of the immune response can mediate activity of another branch of the system.  It is complicated though as it has been shown that influenza proteins can inhibit the production of IFN, which would also inhibit the activation of the IFN receptors and subsequent products.

Secondary pneumococcal infection also only occurs in a subset of individuals so there are still parts of this story that need to be elucidated.  But this does give immunologists a working model for this system of infections and as can be seen from the case in Brazil maybe help to stop further infections in the future.

Shahangian, A., Chow, E., Tian, X., Kang, J., Ghaffari, A., Liu, S., Belperio, J., Cheng, G., & Deng, J. (2009). Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice Journal of Clinical Investigation, 119 (7), 1910-1920 DOI: 10.1172/JCI35412


Since the FDA recalled Nestle’s cookie dough products E. coli O157:H7 is again in the news.  Today I thought I’d cover a topic that I am pretty familiar with, exactly how this strain of E. coli can be so damaging to the body.

E. coli O157:H7 is  a nasty little bacteria that I worked with quite a bit in my microbiology days. The letter/number combination after E. coli just indicate its strain.  Just as all dogs are the same species but can be classified into breeds, bacteria have this distinction as well.

This particular strain of E. coli produces a protein (Shigella-like toxin) that causes damage and death to cells in our body and has been in the news a lot as it has broken out in the food chain from several different locations. Usually patients will have diarrhea and recover just fine, but in some patient the infection can lead to a condition called Hemolytic Uremic Syndrome (HUS), which in severe cases can require long-term dialysis or a kidney transplant. So exactly what is going on when you get infected with this strain of E. coli and how is it that a bacteria in the gut can cause kidney damage?

After you ingest the bacteria it begins a search for a suitable home along the lining of the intestine.  By employing a protein called intimin to bind the inestinal mucosa the bacteria can resist attempts of the host to expel it.  As the little bugger becomes attached to the intestinal cells it disrupts the brush border which leads to the most common symptom, diarrhea.

After the colony has settled in, the production of Shigell-like toxin 2 (Stx-2) begins and the real damage can start.  Stx-2 migrates across the intestinal cells and is released into the blood stream.  Here it binds with polymorphonuclear leukocytes (PMNs) and is carried around in the blood stream on these cells.  The Stx-2 receptor on PMNs isn’t very strong though and as they are pushed passed the glomerulus in the kidneys a new player emerges.screen-capture-2

The Stx-2 receptor on glomerular endothelial cells (Gb3) has a much higher affinity (100-fold) for the Stx-2 protein than do the receptors on the PMNs, so as the PMNs wizz past these Gb3 containing cells the Stx-2 changes dance partners and attaches to the much stronger receptor in the kidney cells.  The E. coli hanging out in your intestines have sent a long-range missile with an advanced targeting system directly to your kidneys endothelial cells.

Once docked onto the cell membrane Stx-2 is endocytosed and moves towards its target inside the cell, the ribosome.  By attaching to the 28S rRNA compnoent it can affectively alter and shut down protein production within the cell.  There are a few ways that this can cause damage to the endothelial cells; one way is by shutting down protein production enough that the cell cannot maintain its metabolism and eventually dies, or certain mediators which are vasoactive can become disregulated (such as Nitric Oxide) which can cause microvascular damage.

As the regulation of these mediators is thrown off a cascade of events starts, including abnormal leukocyte-endothelial adhesion and misregulated production of the coagulation cascade proteins.  This all leads to complications in the microvasculature of both the gastrointestinal and renal system.

It is fascinating that a bacteria who reside in the gut (which is technically outside of the body) can have some wide reaching effects without actually entering the body proper.  This is a great example of the extremely complicated processes that can occur during infections in the body.