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Experiments found that wounds infected with E. faecalis (seen here) had dampened immunity, allowing E. faecalis to persist and enabling co-infecting bacteria like E. coli to thrive. A mouse model allowed researchers to study how lactic‑acid‑driven immune suppression promotes persistent, polymicrobial infections.
Image Credit: Janice Haney Carr / Centers for Disease Control and Prevention
Scientific Frontline: Extended "At a Glance" Summary: Bacterial Immune Suppression in Chronic Wounds
The Core Concept: Enterococcus faecalis (E. faecalis) is a highly resilient bacterium that suppresses the body’s initial immune defenses in wounds by releasing large amounts of lactic acid. This localized acidification deactivates key immune cells, allowing E. faecalis and other co-infecting microbes to establish persistent, hard-to-treat infections.
Key Distinction/Mechanism: Unlike bacteria that simply resist antibiotics, E. faecalis actively sabotages the host immune system through a targeted, two-step mechanism. The secreted lactic acid enters macrophages via the MCT-1 lactate transporter and simultaneously binds to the GPR81 lactate-sensing surface receptor. Engaging both pathways effectively shuts down the macrophage's downstream inflammatory response by preventing the activation of NF-κB, a critical intracellular immune alarm signal.
Major Frameworks/Components:
- Microenvironmental Acidification: The use of bacterial lactic acid to actively lower wound pH and alter the local tissue environment.
- Macrophage Deactivation: The direct targeting and suppression of the primary immune cells responsible for initiating the clearance of pathogens.
- Receptor-Mediated Silencing: The specific engagement of MCT-1 and GPR81 pathways to block intracellular immune signaling.
- NF-κB Inhibition: The molecular silencing of the host's fundamental "danger" alarm network.
- Polymicrobial Facilitation: The cascade effect wherein the dampened localized immunity creates an opportunistic environment for secondary pathogens, such as Escherichia coli, to rapidly colonize and proliferate.
Branch of Science: Microbiology, Immunology, and Infectious Disease Pathology.
Future Application: This discovery lays the groundwork for novel, non-antibiotic treatments for chronic wounds. Future therapies could focus on topically reducing wound acidity or developing pharmacological inhibitors that block the lactic acid signaling pathways, thereby "switching back on" the host's natural immune cells.
Why It Matters: Chronic wound infections—such as diabetic foot ulcers and post-surgical complications—pose a massive burden on global health care systems and frequently result in amputations. Understanding that these infections persist due to active immune suppression, rather than mere antibiotic resistance, shifts the paradigm of wound care toward immune-supporting therapies and targeted pH management.
Chronic wound infections are notoriously difficult to manage because some bacteria can actively interfere with the body’s immune defenses. In wounds, Enterococcus faecalis (E. faecalis) is particularly resilient — it can survive inside tissues, alter the wound environment, and weaken immune signals at the injury site. This disruption creates conditions where other microbes can easily establish themselves, resulting in multi-species infections that are complex and slow to resolve. Such persistent wounds, including diabetic foot ulcers and post-surgical infections, place a heavy burden on patients and health care systems, and sometimes lead to serious complications such as amputations.
Now, researchers have discovered how E. faecalis releases lactic acid to acidify its surroundings and suppresses the immune-cell signal needed to start a proper response to infection. By silencing the body’s defenses, the bacterium can cause persistent and hard-to-treat wound infections. This explains why some wounds struggle to heal, even with treatment, and why infections involving multiple bacteria are especially difficult to eradicate.
The work was led by researchers from the Singapore-MIT Alliance for Research and Technology (SMART) Antimicrobial Resistance (AMR) interdisciplinary research group, alongside collaborators from the Singapore Centre for Environmental Life Sciences Engineering at Nanyang Technological University (NTU Singapore), MIT, and the University of Geneva in Switzerland.
In a paper titled “Enterococcus faecalis-derived lactic acid suppresses macrophage activation to facilitate persistent and polymicrobial wound infections,” recently published in Cell Host & Microbe, the researchers documented how E. faecalis releases large amounts of lactic acid during infection. This acidity suppresses the activation of macrophages — immune cells that normally help to clear infections — and interferes with several important internal processes that help the cell recognize and respond to infection. As a result, the mechanisms that cells rely on to send out “danger” signals are suppressed, leaving the macrophages unable to fully activate.
Researchers found that E. faecalis uses a two‑step mechanism to achieve this. Lactic acid enters the macrophages through a lactate transporter called MCT‑1 and also binds to a lactate-sensing receptor, GPR81, on the cell surface. By engaging both pathways, the bacterium effectively shuts down downstream immune signalling and blocks the macrophage’s inflammatory response, allowing E. faecalis to persist in the wound much longer than it should. Specifically, the lactic acid prevents a key immune alarm signal, known as NF-κB, from switching on inside these cells.
This was proven in a mouse wound model, where strains of E. faecalis that could not make lactic acid were cleared much more quickly, and the wounds also showed stronger immune activity. In wounds infected with both E. faecalis and Escherichia coli, the weakened immune response caused by lactic acid also allowed E. coli to grow better. This explains why wound infections often involve multiple species of bacteria and become harder to treat over time, particularly since E. faecalis is among the most common bacteria found in chronic wounds.
“Chronic wound infections often fail not because antibiotics are powerless, but because the immune system has effectively been ‘switched off’ at the infection site. We found that E. faecalis floods the wound with lactic acid, lowering pH and muting the NF‑κB alarm inside macrophages — the very cells that should be calling for help. By pinpointing how acidity rewires immune signalling, we now have clear targets to reactivate the immune response,” says first author Ronni da Silva, research scientist at SMART AMR, former postdoc in the lab of co-author and MIT professor of biology Jianzhu Chen, and SCELSE-NTU visiting researcher.
“This discovery strengthens our understanding of host-pathogen interactions and offers new directions for developing treatments and wound care that target the bacteria’s immunosuppressive strategies. By revealing how the immune response is shut down, this research may help improve infection management and support better recovery outcomes for patients, especially those with chronic wounds or weakened immunity,” says Kimberly Kline, principal investigator at SMART AMR, SCELSE-NTU visiting academic, professor at the University of Geneva, and corresponding author of the paper.
By identifying lactic‑acid‑driven immune suppression as a root cause of persistent wound infections, this work highlights the potential of treatment approaches that support the immune system, rather than rely on antibiotics alone. This could lead to therapies that help wounds heal more reliably and reduce the risk of complications. Potential directions include reducing acidity in the wound or blocking the signals that lactic acid uses to switch off immune cells.
Building on their study, the researchers plan to explore validation in additional pathogens and human wound samples, followed by assessments in advanced preclinical models ahead of any potential clinical trials.
Funding: The research was partially supported by the National Research Foundation Singapore under its Campus for Research Excellence and Technological Enterprise program.
Published in journal: Cell Host & Microbe
Authors: Ronni A.G. da Silva, Brenda Yin Qi Tien, Patrick Hsien Neng Kao, Haris Antypas, Cenk Celik, Ai Zhu Casandra Tan, Muhammad Hafiz Ismail, Guangan Hu, Kelvin Kian Long Chong, Guillaume Thibault, Jianzhu Chen, and Kimberly A. Kline
Source/Credit: Massachusetts Institute of Technology | Singapore-MIT Alliance for Research and Technology
Reference Number: mcb040726_01