Pseudomonas bacteria escape immunity by interfering with energy production in macrophages

FWhat lurks in fresh water, hot tub and swimming poolbacteria Pseudomonas aeruginosa When transmitted to humans, it can cause blindness, rashes, and many other symptoms.¹ with short Pathogens acquired in hospitalsThis makes them prone to infecting people who burn or have weakened immune systems, resists multiple antibiotics and fights against the immune system. treatment is difficult.^2,3 In a recent publication e-lifeMolecular microbiologist at Harvard University Lawrence Lame and Arijit Chakraborty They discovered that these bacteria release chemicals that inhibit them. energy generation It is present in the mitochondria of macrophages and weakens the immune response.⁴ This work identified the following new tactics: P. aeruginosa It is used to subvert host immunity and hints at a new approach to treating refractory infections.

one of the chemicals produced Pseudomonascalled 2-Aminoacetophenone (2-AA)It is a useful biomarker. Pseudomonas However, many of its functions, including its effects on innate immune cells, remain unknown.⁵ Previously, Harvard researchers found that: macrophage Do not swallow or dispose of P. aeruginosa– Energy-intensive process – in the presence of 2-AA.⁶ In this study, they explored what mechanisms 2-AA could use to interfere with macrophage function, focusing on how this molecule dampens macrophage bioenergetics.

The team found that laboratory cultures of mouse macrophages inoculated with 2-AA produced less adenosine triphosphate (ATP), a molecule the cells use as an “activator.”energy currency“It funds energy-intensive biochemical reactions.⁷ This confirmed their suspicions that 2-AA impairs cellular energy production. However, multiple pathways produce ATP. Because some pathways produce more ATP than others, we had to pinpoint one 2-AA block to calculate the magnitude of the effect.

There are two main pathways cells use to convert glucose into energy. The first is glycolysis, which occurs in the cytoplasm and produces 2 molecules of ATP per molecule of glucose. Pyruvate, a breakdown product of glycolysis, enters the mitochondria and fuels other energy-generating pathways, namely the Krebs cycle and oxidative phosphorylation. These are produced approx. 30 additional copies of ATP.⁸ Because only oxidative phosphorylation consumes oxygen, the researchers Hippocampus analysis Cellular oxygen uptake is measured using a probe that fluoresces in the presence of this gas molecule.⁹ Cells exposed to 2-AA had reduced oxygen consumption, suggesting that more profitable energy-generating pathways were disrupted.

They also measured the cells’ pyruvate levels.⁸ The presence of 2-AA correlated with higher levels of pyruvate in the cytoplasm, suggesting that pyruvate is unable to move into mitochondria. “So we are not producing as much energy as we would like,” Rahme said.

Because in vitro experiments do not reflect the complexity of the immune system, Rahme and her team sought to verify these findings in live animals. They infected mice with one of the wild types. P. aeruginosa or mutants lacking multiple virulence factor regulators (MvfR) – transcription factor required to express the enzyme that synthesizes 2-AA.¹⁰ Spleen—organ Rich in immune cells—ATP levels decreased within 24 hours in mice infected with wild-type bacteria, but not in mice receiving a mutant lacking 2-AA.¹¹ They observed decreased levels of acetyl cofactor A, a breakdown product of pyruvate formed after entering the mitochondria, confirming that the decrease in ATP was due to a blockage of the energy-generating pathway. They also evaluated the effect of 2-AA on the bacterial burden in the spleen. By day 10, the mice were able to kill the bacteria more easily in the absence of this chemical.

like Pseudomonas As bacteria become increasingly resistant to antibiotics, researchers must develop different types of treatments to treat them.³ Cayenne VadakanSt. Petersburg, Thrissur, who did not participate in the study. A St. Mary’s College microbiologist suggested that 2-AA could serve as a new bull’s eye for drugs to target. “We can complement our immune system,” he said, suggesting that drugs that block the effects of 2-AA could strengthen macrophages. Rahme’s lab is studying this treatment approach. “We are very excited because the MvfR inhibitor we developed works quite well,” she said, referring to additional research not included in this study. However, more studies must be done to evaluate its efficacy and safety before it can be used in clinical practice.

In addition to blocking 2-AA to fight bacteria, researchers could theoretically harness it to prevent autoimmune diseases. In some disorders, such as Rheumatoid arthritis and lupusHyperactive macrophages worsen inflammation.¹² “2-AA is a molecule that acts essentially as an anti-inflammatory,” Chakraborty said, suggesting it may have potential as an immunosuppressant.

Conflict of interest disclosure: Study co-author Laurence Rahme has a financial interest in Spero Therapeutics, a company developing treatments to treat bacterial infections.