Have you ever wondered how our body recognizes when it’s being invaded by harmful bacteria? Nearly all forms of life—from single-celled organisms all the way to humans—have an “innate” immune system, which has evolved to recognize cellular components shared by broad groups of pathogens. One such example is peptidoglycan, a molecule found on the cell walls of virtually all bacteria. Peptidoglycan forms a sort of “load-bearing mesh” required for the bacteria to maintain their shape and is therefore an essential part of their structure. As a result, our immune systems have evolved to recognize peptidoglycan as a danger signal and will trigger an immune response when it is detected.

But just as our innate immune system has evolved to recognize invaders bearing peptidoglycan, bacteria have also evolved to escape detection. In a recent paper published in eLife by the Filipe lab, researchers used fruit flies to study how some bacteria can remain undetected by its host. Understanding how bacteria avoid detection will help us develop new ways to defeat them by preventing them from evading our immune system. This could reduce the need for antibiotics, which is particularly important now that antibiotic-resistant bacteria are becoming painfully common (in 2014, the World Health Organization declared antibiotic resistance a major threat to public health).

The difference between Gram-negative and Gram-positive bacteria. The difference between Gram-negative and Gram-positive bacteria. Image source

So how do bacteria with peptidoglycan conceal themselves from our immune system? Previous work has categorized bacteria into two groups based on the way they cover up their peptidoglycan mesh: Gram-negative bacteria, which have a full membrane surrounding the peptidoglycan molecules, and Gram-positive bacteria, which have the mesh directly outside the cell wall. Instead of a full membrane, Gram-positive bacteria have layers of molecules that stick out of the cell wall and block access to the peptidoglycan. Because of this, it has long been thought that the immune system can only detect peptidoglycan when fragments have been snipped off of the bacterial walls (when bacteria need to grow and divide, they must break down their mesh and then rebuild it).

But now, researchers have uncovered a new twist to this story. Recent findings have suggested that under certain conditions, the immune system can actually recognize peptidoglycan while it’s still a part of the bacterial cell wall. So the authors of this paper asked: Have bacteria evolved other methods to prevent this from happening?

To answer this question, they infected fruit flies with Staphylococcus aureus (S. aureus), a Gram-positive strain of bacteria related to MRSA. They observed how well the fruit fly hosts were able to defend against the invaders, and then mutated parts of the bacteria to determine how each manipulation affected the hosts’ ability to survive. The authors learned that S. aureus releases a molecule called Atl, which they found was responsible for trimming off pieces of peptidoglycan that stick up above the bacteria’s protective layer. When the bacteria couldn’t release Atl, the flies were much more likely to survive the infection because their immune system could more easily recognize the intruders and fight them off.

How can this help us humans? The mammalian innate immune system is similar to that of flies, and also recognizes peptidoglycan as a trigger for activating an immune response. Thus, if bacteria that infect humans use the same evasive maneuvers, it could be possible to develop a drug that targets and disables Atl and other peptidoglycan-snipping molecules. This would allow our immune systems to better recognize and fight back against bacterial infections and reduce the need for antibiotics.

The authors have already done some of the work toward this goal. To find out if strains of bacteria known to endanger humans use the same avoidance mechanism, they also infected flies with MRSA, a dangerous antibiotic-resistant strain of bacteria often found in hospitals, and Streptococcus pneumoniae, which is a frequent cause of pneumonia in developed countries and a major cause of infant mortality in developing countries. That found that both of these bacteria use Atl to shave their surface and avoid recognition by the immune system. Future research may therefore lead to treatments that prevent these bacteria from going into hiding, allowing our immune system to hunt them down and do its job with ease.

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