Researchers at the Institute of Food Research and the University of Leeds have uncovered a mechanism our bodies use to fight off invading bacteria like Salmonella. It may also help to maintain the balance of good bacteria in our gut.
The lining of our gut is a battleground where we have to constantly fight to keep invading disease-causing bacteria out, whilst keeping under control the populations of beneficial bacteria. One line of defence our bodies use are antimicrobial proteins (AMPs) that kill off bacteria. This new study, published in the journal PLOS ONE, describes some of the first evidence for a mechanism of how we detect and activate these defences.
AMPs are kept locked up safely in granules in specialist Paneth cells, found in crypts in the lining of our gut. Paneth cells are fast acting and release the AMPs quickly, but until now we haven’t had a handle on exactly how they are triggered.
The gut lining, being a key barrier between us and the outside world, plays a major role in our immune system, and the gut lining contains populations of immune cells. The researchers at the IFR investigated whether a certain class of lymphocyte cells, called iIELs, were involved. iIELs are the closest populations of immune cells to the gut lining itself, and so are best placed to initiate a response to potentially harmful microbes. iIELs are found in almost all mammals, and their absence results in increased susceptible to infection. But how this happens wasn’t known.
Dr Isabelle Hautefort
The researchers, funded by the Biotechnology and Biological Sciences Research Council and The Wellcome Trust, compared AMP expression in normal mice and in mice lacking iIELs. This identified one particular AMP, angiogenin 4 (Ang 4). They tested Ang 4 under conditions mimicking that in the gut and it effectively kills Salmonella, by disrupting the bacterial cell membranes.
These studies were aided by developing a novel way of growing intestinal tissue and immune cells together. iIELs on their own are sufficient to trigger Ang4 production by Paneth cells, and this happens very quickly. In response to Salmonella, intestinal epithelial cells produce cell signalling molecules called cytokines of which one, IL‑23, triggers iIELs to produce another, IL-22, which in turn triggers Paneth cells to produce Ang4. Understanding this signalling pathway is a key step in understanding how our immune system communicates with epithelial cells in the intestine to protect us from invasion.
The researchers also found that this same signalling pathway is also triggered by some of the beneficial, commensal, bacteria inside of us. This may be a mechanism to keep their populations in check and maintaining the healthy balance between all of the different species. Although our bodies actively encourage the colonisation and survival of the beneficial bacteria, crossing the lining of the gut and entering the blood stream may cause other illnesses.
Intestinal Intraepithelial Lymphocyte-Enterocyte Crosstalk Regulates Production of Bactericidal Angiogenin 4 by Paneth Cells upon Microbial Challenge. PLoS ONE 8(12): e84553. doi:10.1371/journal.pone.0084553