Antibacterial contact |  Max Planck Society

How does the interaction between lysosomes and mitochondria limit the growth of Salmonella in macrophages

Macrophages play a central role in our immune system. They trap invading pathogens in the body and digest them inside. However, some bacteria such as salmonella or mycobacteria are able to resist the gastrointestinal tract of macrophages known as lysosomes and thus avoid the attack of immune cells. Research conducted by the Max Planck Institute for Immunology and Epigenetics in Freiburg shows how different organelles of macrophages communicate with each other in order to activate a particularly effective antibacterial defense mechanism. Thus, the successful elimination of certain types of bacteria depends on a signal transmitted by the phago-lysosomal system to another organ system, the mitochondria. This hitherto unknown interaction between lysosomes and mitochondria within immune cells could provide new starting points for better control of infectious diseases.

Macrophages are one of the most important defensive cells of the innate immune system. It is found in almost every tissue in our body and plays an indispensable role in the health of our organs, as it constantly removes dying cells and removes microbes that have invaded the tissues. Macrophages are considered professional scavenger cells because they are particularly good at absorbing and destroying and thus eliminating foreign matter and pathogens.

However, certain bacteria, such as salmonella, have developed strategies to evade digestion within macrophages, causing acute inflammation such as typhoid. In their latest study, scientists at the Max Planck Institute for Immunology and Epigenetics in Freiburg showed how the interaction between two organelles, lysosomes and mitochondria, prevents the growth of these bacteria in macrophages.

Signals from the cellular digestive system

Like most other cells, the interior of the macrophage is divided into several different divisions. These cell subunits, known as “organelles,” each perform specific functions, similar to organ systems in humans, which perform specialized tasks in the body. As scavenger cells, macrophages possess a very distinct digestive organelle, the lysosomal phage, in which the microorganisms normally disintegrate into pieces and thus inactivated. “It has long been known that the protein TFEB, in its function as a transcription factor, plays an important role in controlling the phago-lysosomal system. Recent findings also show that TFEB is also important in defense against bacteria,” says Max Planck Group Leader Angelica Rumbold Study leader.

She and her research team wanted to discover exactly how TFEB mediates this antibacterial role in macrophages. They initially confirmed previous findings that a wide range of microbial, bacterial, and inflammatory signals activate the TFEB protein and the phago-lysosomal system. “It was logical that the pathogenic and inflammatory signals activate TFEB. Finally, after ingestion of bacteria, macrophages require a more active digestive system. However, it is interesting that our experiments also showed a remarkable effect of TFEB activation on another intracellular organ system – mitochondria. That was Completely unexpected and new to us,” says Angelica Rumbold.

Mitochondrial Instructions: Raise the Quality of Antimicrobials

Mitochondria are often referred to as the “centers of cell power”. These organelles consist of an inner and an outer membrane, and are the primary site of cellular respiration, where energy is released to the cell from the nutrients supplied. However, mitochondria also function in immune cells as a source of antimicrobial metabolites.

Using a wide range of experimental techniques such as metabolism and various imaging techniques, the team was able to identify the exact signaling pathway that controls the interaction between lysosomes and mitochondria. “During the immune response, macrophages use an interesting organic signaling cascade: the lysosome activates TFEB, which then migrates into the cell nucleus, where it regulates the transcription of a protein called IRG1. This protein, in turn, is inserted into the mitochondria, where it acts as a key enzyme for anti-metabolite production. for microbes,” explains Angelica Rumbold.

Use of organic contact to control bacterial infections

The researchers continued to investigate whether they could harness a newly identified signaling pathway to control bacterial growth. “We suspected that activation of this signaling pathway could be used to inhibit certain bacteria, such as salmonella,” says Angelica Rumbold. “Salmonella can escape decomposition through the phago-lysosomal system. They were able to grow inside the macrophages, which could lead to the distribution of these bacteria to multiple organs in the affected body,” explains co-author of this study, Alexander Westermann, a group leader at Helmholtz HIRI and a junior professor at the University of Würzburg. When researchers activated TFEB in Infected murine macrophages, the TFEB-Irg1-itaconate signaling pathway inhibited salmonella growth in cells These data indicate that the interaction between lysosomes and mitochondria constitutes an antibacterial defense mechanism designed to protect macrophages from being misused as a bacterial growth region.

In light of the increasing prevalence of multi-resistant bacteria, experts predict more than ten million deaths worldwide by 2050. It is therefore very important to find new strategies to combat bacterial infections that do not control natural immunity. Pharmacological use of the TFEB-Irg1-itaconate signaling pathway or itaconate itself could be a promising avenue for treating infections caused by bacteria sensitive to itaconate. According to the scientists from Freiburg and Würzburg, however, further investigation is needed to determine if these new starting points can also be used successfully in humans.



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