When they encounter bacterial invaders, some human cells dispense an amazing substance: soap.
These cells, which are not part of the immune system, trigger a detergent-like protein that dissolves pieces of the bacteria’s inner membranes, killing infiltrators, researchers reported in the July 16 issue of the journal Science.
“Professional” immune cells, such as antibodies or white blood cells, receive a lot of attention, but “all cells are endowed with a certain ability to fight infection,” says John MacMicking, an immunologist at Yale University.
In humans, these cellular defenses have often been ignored, MacMicking says, although they are part of an "ancient and primordial defense system" and could inform the development of treatments for new infections.
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Often, non-immune cells rely on a warning from their professional counterparts to fight infections. Upon detecting people from outside, specialized immune cells release an alarm signal called interferon gamma. That signal causes other cells, including the epithelial cells lining the throat and intestines, and are often directed by pathogens, to action.
MacMicking and colleagues sought the molecular basis for this action by infecting laboratory versions of human epithelial cells with Salmonella bacteria, which can exploit the nutrient-rich interior of cells. The team then examined more than 19,000 human genes, looking for those that confer some protection against infection.
He highlighted a gene, which contains instructions for a protein called APOL3. When this gene was inactivated, epithelial cells succumbed to a Salmonella infection, even when they were warned by interferon gamma. By approaching APOL3 molecules in action within host cells with high-power microscopy, the researchers found that the protein swarms the bacteria and somehow kills them.
R.G. Gaudet et al / Science 2021
Salmonella are resistant microbes, protected by an outer and inner membrane, a feature shared by many different forms of bacteria. This double layer makes these bacteria difficult to kill, but later research has revealed how APOL3 and another molecule, GBP1, work together to do so. GBP1 somehow loosens the bacterium’s outer membrane, opening doors for APOL3 to deliver its death by dissolution to the inner lipid membrane. APOL3 has water-loving and lipid-loving parts, letting it attach to the inner membrane and dissolve it in the intracellular fluid, like soap that removes fat.
“We were a little surprised to find detergent-like activity within human cells,” MacMicking says, given that such a molecule could also dissolve host membranes. But the researchers found that APOL3 specifically targets lipids found in bacteria and that its activity is blocked by cholesterol, a common component of mammalian cell membranes, leaving human tissues affected.
“Everything about these findings is super cold,” says Jessica Brinkworth, an evolutionary immunologist at the University of Illinois Urbana-Champaign who did not participate in the study. Many infections begin in these epithelial cells and understanding how they fight is crucial to developing future treatments, she says.
“The really interesting finding is how APOL3 is able to distinguish between bacterial membranes and host membranes,” she says. That evolution has found such an elegant way to control this powerful tool “it’s a beautiful thing”.