The antimicrobial protein produced by the body’s normal cells destroys the lipid-like components of the bacterial cell wall, just as washing-up actives do on fat stains.
Active laundry detergents contained in cleaning agents not only dissolve grease, but also have an antimicrobial effect: they penetrate the lipid layer of cell membranes and thus can kill viruses and bacteria. US doctors have now discovered that bacteria that have invaded human cells produce a protein that works in a similar way against pathogens. Supported by other antibacterial agents, the researchers reported in the journal Science that APOL3 lipoprotein destroys the double-membrane cell wall of Salmonella and other Gram-negative bacteria. A better understanding of this form of so-called cellular-independent immune defense, which operates independently of immune cells, could help develop new treatments against infection.
“In this case, humans produce their own antibiotic in the form of a protein that acts as a cleaner,” says John MacMicking of Yale University in New Haven. When pathogens enter our bodies, they release alarm signals that activate, on the one hand, the immune system. On the other hand, one of the messengers, interferon-gamma, also turns on many of the genes of the body’s normal cells, as these cells set their own defense mechanisms in motion. While skin cells and mucous membranes release antimicrobial peptides to attack extracellular pathogens, other defensive actions are required when bacteria have already invaded the inside of the cell.
Using human cell cultures, MacMicking and colleagues investigated which genes are activated by interferon gamma. One of about 19,000 genes identified caused the production of apolipoprotein APOL3 in cells of various tissues. As with detergents, the molecular structure of this protein showed a water-soluble and lipid-soluble section. With the lipid-soluble part of the molecule, the protein can penetrate the lipid-like lipid layer of biological membranes, which leads to the breakdown of the membrane structure. The researchers were able to make this directly visible with the help of special live microscopy techniques when they infected the cells with Salmonella (Salmonella enterica serovar Typhimurium). When the outer bacterial membrane was damaged by other factors, APOL3 disintegrated the inner membrane into small pieces. In doing so, the cell has to protect its own membranes: the usual cholesterol content in human membranes and some components of bacterial membranes ensure that the attack is directed against bacteria only. APOL3 was only effective against those Gram-negative bacteria that invade the cytoplasm of body cells during infection.
Commenting on the research, Carl Nathan of Weill Cornell Medical College said: “The results confirm the view that every cell in the body can be part of the immune system.” Cell membrane disintegration is one of the few ways to kill pathogens, along with membrane perforation, starvation and poisoning. More research could enable new treatments that support the body’s natural immune response to infection. This will be even more important as more and more pathogens are becoming resistant to available antibiotics.