Cells attack invading bacteria with a kind of detergent, researchers report: Similar to how detergents remove grease stains, the protein called APOL3 dissolves lipids from the pathogen’s shells and kills them, according to the studies. The new insights into the cells’ arsenal of weapons could help the development of new strategies in the fight against pathogens, say the scientists.
Without the immune system, all hell would break loose in our bodies: Bacteria in particular have to be kept in check, otherwise they will multiply explosively and destroy the tissues. As is known, special immune cells function in the body as body police, which locate and eliminate the bad guys. However, the individual cells of our body can also defend themselves against intruders through certain mechanisms. This so-called cell-autonomous immunity forms one of the foundations of our body’s defense system. It is also already known that the alarm signaling substance interferon gamma not only activates the immune cells in the body, but also these cellular defense systems. But what specific substances the cells then form to protect against bacteria has so far hardly been researched.
Scientists working with John MacMicking from Yale University in New Haven have now investigated this question. As part of their study, they first examined genes that are activated in human cell cultures by the action of interferon gamma. Using molecular genetic methods, they then characterized some of these genetic makeup or the substances for which they code. So they finally came across the protein APOL3, whose production is boosted by the alarm signal interferon gamma. It piqued particular interest from researchers, as these proteins are normally known to dissolve lipids for extracellular transport.
Dissolved bacterial envelopes
In order to investigate the function of APOL3 in the context of cell-autonomous immunity, the scientists marked the protein and examined how it reacts when salmonella penetrate cells. The investigations using high-resolution microscopy and other techniques showed: First of all, additional molecules apparently enable APOL3 to overcome the outer membrane of the double shell of Salmonella. The inner membrane can then be tampered with: the protein dissolves it and thereby kills the bacteria. As the researchers explain, APOL3 has the same characteristics as a detergent: Similar to the way they dissolve fats through their chemical properties, the protein tears the bacterial membrane into pieces because it consists of “fatty” molecules – the so-called lipids.
But why doesn’t APOL3 also attack the lipids of the cell itself? The team found that the detergent avoided cholesterols, which are a major part of human cell membranes. Instead, it binds to the characteristic lipids that are found in the coats of bacteria, the scientists explain. “We have thus documented a case in which humans produce their own antibiotic in the form of a protein that acts like a cleaning agent,” MacMicking sums up. The scientists say that the APOL3 is probably a standard weapon in the arsenal of many cells in the body. So far, they have already been able to show that, in addition to the skin, it is also active in the cells of the blood vessels and the intestines.
Fundamental potential for medicine
The new findings are an important contribution to the understanding of cell-autonomous immunity, says Carl Nathan from Weill Cornell Medical College in New York in recognition of the results of his colleagues. “The discovery of this detergent-like molecule supports the view that every cell in the body can be part of the immune system,” comments the immunologist. “It shows that various control strategies have emerged to kill threatening pathogens. APOL3 now joins the group of mechanisms that are already known to destroy membranes, ”says Nathan.
Researchers are still a long way from being able to apply this discovery to therapies against infections. But as they emphasize, it is an important contribution to basic research: “The deciphering of the body’s own defenses could one day provide mankind with new tools against microbes, which are increasingly developing ways to bypass conventional antibiotics. Targeting the production of cellular detergents or other agents that the body uses to kill bacteria could complement the natural immune response, ”says MacMicking.
Source: Howard Hughes Medical Institute, Article: Science, doi: 10.1126 / science.abf8113