Enterococcus faecalis biofilm rewires neutrophil metabolism to suppress antimicrobial activity

In the human body, the immune system maintains a constant, vigilant watch against invaders. Among its most rapid and numerous defenders are neutrophils, a type of white blood cell that acts as a first responder to infection. When these cells detect a threat, they rush to the site and deploy a variety of weapons to neutralize the enemy. One of their most potent tactics involves engulfing bacteria to destroy them internally, while another involves releasing a web-like net of DNA and toxic proteins to trap and kill microbes from the outside. However, some bacteria have evolved to survive even in the presence of these powerful defenses, particularly when they organize themselves into dense, slimy communities known as biofilms. These structures allow bacteria to cling to surfaces and resist being washed away or eaten, turning a simple infection into a persistent, difficult-to-treat problem. Understanding how these microscopic communities manage to silence the immune system is crucial for developing new ways to treat stubborn infections that do not respond to standard therapies.

A team of researchers recently turned their attention to Enterococcus faecalis, a common bacterium that often causes serious infections in hospitals, especially when it forms these protective biofilms. Despite the body sending large numbers of neutrophils to fight these infections, the bacteria often persist. The scientists wanted to understand the specific mechanism behind this evasion: how does a biofilm of E. faecalis stop neutrophils from doing their job? By studying human neutrophils in the laboratory and observing the infection process in mice with skin wounds, the researchers discovered that the bacteria actively rewire the metabolism of the immune cells, effectively disarming them before they can attack.

The study revealed that when neutrophils encounter a biofilm of E. faecalis, their ability to perform critical functions is severely compromised. Instead of trapping the bacteria in nets or swallowing them whole, the immune cells become sluggish and ineffective. The researchers traced this failure back to the metabolic activity of the bacteria themselves. E. faecalis produces an enzyme called lactate dehydrogenase, which helps the bacteria break down sugars. In the process, this enzyme generates lactic acid, which accumulates in the space around the bacteria. This buildup of acid creates a harsh, acidic environment that lowers the pH level inside the neutrophils. This shift in acidity disrupts the cell's internal energy production, specifically interfering with the pathways the cell uses to convert sugar into fuel, such as glycolysis and the tricarboxylic acid cycle. Without a steady supply of energy, the neutrophils cannot generate the power needed to release their defensive nets or to engulf the bacteria.

To confirm that this lactic acid production was the key factor, the scientists conducted experiments where they removed the gene responsible for making the lactate dehydrogenase enzyme. In these modified bacteria, the production of lactic acid stopped, and the acidic environment did not form. When these altered bacteria were introduced to neutrophils, the immune cells remained healthy and functional. In a mouse model of wound infection, the loss of this enzyme led to a significant increase in the number of neutrophils recruited to the wound and a restoration of their ability to release defensive nets. This demonstrated that the bacteria's ability to acidify their surroundings was a primary driver of immune suppression.

However, the researchers also found that the story was not entirely about acid. They observed that even when the bacteria could not produce lactic acid, a very high density of bacterial cells—characteristic of a mature biofilm—still managed to suppress the formation of immune nets. This indicated that the sheer physical crowding of the bacteria, independent of the chemical acid they produce, also plays a role in dampening the immune response. The findings suggest that E. faecalis employs a dual strategy to evade the immune system: it chemically disables the energy supply of neutrophils through acid production, while its dense, crowded structure provides an additional layer of protection that further hinders immune activity. These insights highlight how the metabolic habits and physical organization of a bacterial community can work together to outmaneuver the body's natural defenses.