Unfortunately, if used often, antibiotics end up not being efficient anymore, because our body develops resistance to drugs, and that is why we must always look for new ones. But a surprising cellular defense strategy could inspire a new category of antibiotics.
Faced with bacterial invaders, some human cells dispense a surprising substance: soap. These cells, which are not part of the immune system, release a detergent-like protein that dissolves pieces of the bacteria’s inner membranes, killing infiltrates, according to researchers who published it today in Science.
The immune cells “Professional”, like antibodies or white blood cells, get a lot of attention, but “All cells have a certain ability to fight infections”says John MacMicking, an immunologist at Yale University.
In humans, these ordinary cellular defenses have often been overlooked, MacMicking says, even though they are part of “An ancient and primordial defense system” and could make a difference in developing treatments for new infections.
Often, non-immune cells they rely on a warning from their professional counterparts to fight infections. Upon detecting strangers, specialized immune cells release an alarm signal called interferon gamma. That signal stimulates other cells, including the epithelial cells that line the throat and intestines and are often targeted by pathogens, to take action.
MacMicking and colleagues sought the molecular basis for this action by infecting laboratory versions of human skin cells with Salmonella bacteria, which can exploit the nutrient-rich interior of the cells. Then, the team examined over 19,000 human genes, looking for those that had gained some protection from infection.
Targeted and specialized antibiotics
One gene, which contains the instructions for a protein called APOL3, has stood out. When this gene was turned off, the epithelial cells succumbed to a Salmonella infection, even when sensed by interferon gamma. By zooming in on APOL3 molecules in action inside host cells with a high-powered microscope, the researchers found that the protein it invaded the bacteria in swarms and somehow killed them.
Salmonella microbes are very resistant, protected by an outer and inner membrane, a feature shared by many different forms of bacteria. This bilayer makes these bacteria difficult to kill, but further investigation revealed how APOL3 and another molecule, GBP1, work together to do so.
GBP1 somehow loosens the outer membrane of the bacteria, opening the doors to APOL3 which dispenses its death by dissolution in the inner lipid membrane. APOL3 has both water-loving and lipid-loving parts, allowing it to bind to the inner membrane and dissolve it in the intracellular fluid, like soap that washes away fat, thanks to surfactants.
“We were a little surprised to find a detergent-like activity within human cells”MacMicking says, as such a molecule could dissolve host membranes as well. But the researchers found that APOL3 specifically targets lipids found in bacteria and its activity is blocked by cholesterol, a common component of mammalian cell membranes. leaving human tissues unaltered.
“Everything in these results is fantastic”says Jessica Brinkworth, an evolutionary immunologist at the University of Illinois Urbana-Champaign who was not involved in the study. Many infections start in these skin cells and understand how they react it is crucial for the development of future treatments, he claims.
“The really interesting discovery is how APOL3 is able to distinguish between bacterial membranes and host membranes”, he claims. Evolution has found such an elegant way to control this powerful tool “it’s a beautiful thing”.
The sensational thing is that it will then be possible to decrease resistance to antibiotics, no longer using mold as a basic active ingredient, and moreover, targeted and non-broad-spectrum treatments will not be possible, reducing side effects.