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We do not live by bread alone. To digest the bread, as well as the rest of the food we consume, our bodies resort to the help of microbes that live in our gut. These number in the billions; their total weight adds up to nearly two kilograms. Most are friendly and, as noted, even vital for the normal functioning of digestion and other body systems. But occasionally, disease-causing microbes such as Salmonella sneak in among them.
In most cases, the immune system identifies and destroys the dangerous microbes so that we do not even know we’d been exposed to the risk. But how does the system tell the good microbes from the bad? How does it detect the danger? The task is far from trivial: The microbes are contained in the gut, whereas the immune cells are embedded in the gut lining, the epithelium. Complicating detection even further, the few harmful bacteria present in a healthy gut are vastly outnumbered by the rest of the gut flora.
A team of Weizmann Institute scientists headed by Dr. Guy Shakhar of the Immunology Department recently shed light on this mystery. As reported in the journal Immunity, the scientists showed that the immune system sends its “spies,” so-called dendritic cells, to the surface of the gut lining. The research was performed by graduate student Julia Farache, along with her lab-mates Idan Koren, Idan Milo and Dr. Irina Gurevich; Drs. Ki-Wook Kim and Ehud Zigmond from Prof. Steffen Jung’s lab in the same department; and researchers from the Mt. Sinai School of Medicine in New York: Drs. Glaucia C. Furtado and Sergio A. Lira.
Using a two-photon microscope, the scientists created an innovative setup that enabled them to monitor in real time immune cells in the gut of a live mouse. It turns out that the moment Salmonella bacteria stick to the epithelium of the small intestine, the epithelial cells inform the immune system and, within half an hour, dendritic cells are recruited to the site of the infection. In video clips created under the microscope, these cells can be clearly seen squeezing through crowed tissue to reach the upper layer of the epithelium and sending their extensions – the dendrites for which they are named – to capture the bacteria.
Why do they respond in this manner to Salmonella but not to the millions of “good” bacteria in the same environment? While the beneficial bacteria don’t damage cells because they probably don’t stick to the gut lining, Salmonella signals its intent to harm by latching on to the epithelium.
Having swallowed the bacteria, the dendritic cells rush to report to the immune system. They start expressing receptors that guide them back into the intestinal tissue and through the lymph vessels. In the lymph nodes, they present fragments of Salmonella’s proteins – in other words, the bacterium’s “body parts” – to immune T cells, which turn on mechanisms that destroy the Salmonella, preventing poisoning.
This research may in the future help develop therapies against inflammatory bowel diseases, which are characterized by flare-ups of inflammation. Since dendritic cells are involved in igniting these flare-ups, possibly by overreacting to an infection, understanding their mechanism of action in the gut may help prevent their harmful activity.
Dendritic cells send their extensions (red arrows) between adjacent epithelial cells (blue) in the lining of the small intestine
The new findings may also help develop oral vaccines, which offer major advantages over conventional methods of vaccination; for one, it’s easier to convince people to take a pill than to get an injection. Vaccines consist of weakened microbes, but for them to be effective, the microbes must be weakened in such a manner that they are capable of activating the immune system, yet do not cause disease yet. Therefore, it’s important to understand how microbes communicate with the immune system in the intestines, which is precisely what the current study has helped achieve.
Dendritic cells (brown) capture Salmonella microbes (light blue), then rapidly retract their extensions (arrow)
Prof. Steffen Jung's research is supported by the Leir Charitable Foundations; the Leona M. and Harry B. Helmsley Charitable Trust; the Adelis Foundation; Lord David Alliance, CBE; The Wolfson Family Charitable Trust; and the estate of Olga Klein Astrachan.
Dr. Guy Shakhar's research is supported by the Clore Center for Biological Physics; the Yeda-Sela Center for Basic Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Dr. Dvora and Haim Teitelbaum Endowment Fund; Simone Pastor, Monaco; Lord David Alliance, CBE; Paul and Tina Gardner, Austin, TX; the Steven and Beverly Rubenstein Charitable Foundation; and the Paul Sparr Foundation.
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