Anti-bacterial linker: How communication between lysosomes and mitochondria controls Salmonella growth in macrophages - Azi News

Macrophages are key cells of our innate immune response. By filling up almost all the tissues in our body, these cells have an important role in keeping our organs in a healthy state, as they are constantly removing dead cells or eliminating microbes invading tissues. As cells that specialize in eating and devouring, macrophages are very well adapted to take in, digest, and destroy foreign materials.

However, certain microorganisms and bacteria such as Salmonella have developed strategies to protect themselves from ingesting macrophages, causing severe typhoid infection and inflammation. Scientists from the MPI of Immunobiology and Epigenetics in Freiburg now report in their latest study published in the scientific journal Natural Metabolism how inter-organelle crosstalk between phago-lysosomes and mitochondria limits the growth of these bacteria in macrophages.

Signals from digestive cell organelles

The interior of a macrophage, like most other cells, is divided into different compartments. These so-called “organelles” each take over a specific function within the cell, in analogy to the human organ system, which fulfills a specific role in our body. As professional scavenging cells, macrophages possess a very prominent digestive organelle, the phago-lysosomes, where ingested microorganisms are normally degraded into pieces and become inactive. “It has long been known that the TFEB molecule (EB transcription factor) is important for the regulation of the phago-lysosomal system. More recent evidence also suggests that TFEB supports defenses against bacteria,” said Max Planck group leader Angelika Rambold.

He and his team wanted to understand how exactly TFEB mediates its anti-bacterial role in macrophages. They confirmed previous findings showing that various microbial, bacterial and inflammatory stimuli activate TFEB and thus the phago-lysosomal system. “It makes sense that pathogen signaling triggers TFEB because macrophages need a more active digestive system quickly after they have eaten the bacteria. But, interestingly, the experiments also revealed an additional strong effect of TFEB activation on another intracellular organelle system—mitochondrion. This was completely unexpected and new for us,” said Angelika Rambold.

Instructs mitochondria to increase anti-microbial activity

Mitochondria are best known as the “powerhouse of the cell.” Composed of the inner and outer mitochondrial membranes, this organelle is the main site of cellular respiration and releases energy from nutrients. In addition, mitochondria in immune cells have recently been identified as a source of anti-microbial metabolites.

Using a broad set of experimental tools, including metabolomics, molecular biology, and imaging techniques, the Max Planck researchers identified the pathways that control unexpected cross-talk between lysosomes and mitochondria. “Macrophages make extensive use of inter-organelle communication: lysosomes activate TFEB, which travels into the nucleus where it controls the transcription of a protein called IRG1. This protein is imported into the mitochondria, where it acts as a key enzyme to produce the anti-microbial metabolite itaconate,” explains Angelika Rambold.

Utilizes organelle communication to control bacterial infections

The researchers are exploring whether they can exploit this newly identified pathway to control bacterial growth. “We speculate that activating this pathway could be used to target specific bacterial species, such as Salmonella,” said Angelika Rambold. “Salmonella can escape degradation by the phago-lysosomal system. They manage to grow inside macrophages, which can lead to the spread of these bacteria to several infected organs in the body,” explains Alexander Westermann, a collaborating scientist from the University of Würzburg.

When the researchers activated TFEB on infected macrophages in mice, the TFEB-Irg1-itaconate pathway inhibited Salmonella growth in cells. These data suggest that lysosomal-to-mitochondrial interactions represent an antibacterial defense mechanism to protect macrophages from being exploited as a bacterial growth niche.

Given the increasing emergence of multi-drug resistant bacteria, with more than 10 million deaths expected per year by 2050 according to various expert groups, it becomes important to identify new strategies to control bacterial infections that escape immune mechanisms. Utilizing the TFEB-Irg1-itaconate pathway or itaconate alone to treat infections caused by itaconate-sensitive bacteria may be a promising avenue. According to scientists from Freiburg and Würzburg, more work, however, is needed to assess whether these new intervention points can be successfully applied to humans.

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