How bacteria exploit human cell metabolism to sharpen infections and potentially evade treatment

The top image shows the immunofluorescence staining of ceramide (membrane), DAPI (DNA), and phalloidin (F-actin); the bottom image shows a transmission electron microscopy (TEM) image. Credit: Weinrich & Kozjak-Pavlovix

A research team at the University of Greifswald's Research Training Group RTG-PRO "Proteases in pathogen and host: importance in infection and inflammation" has discovered a new mechanism by which bacterial pathogens adjust their activity to the metabolism of infected host cells. Bacteria tailor their attack to the metabolic state of the host cells and are thus able to specifically regulate their pathogenic effects.

The results of the study, published in Nature Communications , provide important insights into bacterial infection processes. They could have a long-term impact by improving our understanding of infections and providing new approaches in the fight against antimicrobial-resistant pathogens.

Bacterial pathogens can infect various kinds of human cells and trigger serious illnesses. At the same time, the increasing spread of antimicrobial-resistant bacteria is posing significant challenges to hospitals and health care systems across the globe.

A research team led by Prof. Dr. Michael Lammers and lead author Ole Schmöker investigated the virulence factor SnCE1 of the Chlamydia-like bacterial pathogen Simkania negevensis. This bacterium can cause illnesses such as respiratory or pulmonary infections. Virulence factors are specialized proteins that bacteria use to specifically influence human cells.

The pathogens use special transport systems to smuggle these proteins into the host cells. Once there, they modify the cells to facilitate the bacteria's reproduction, making it easier for infections to spread.

SnCE1 reacts to the cell's metabolic state

The research team was able to demonstrate for the first time that the activity of the bacterial protein SnCE1 is directly dependent on the metabolic state of the host cell. The molecule Acetyl-CoA, which plays an important role in providing energy to the cell, is the decisive factor. The greater the amount of Acetyl-CoA, the greater the changes to the structure and function of the protein.

SnCE1 can perform two tasks at the same time: first, it removes SUMO molecules from proteins in the host cell and thus intervenes in important regulatory mechanisms. Second, it can chemically modify itself by attaching acetyl groups to certain amino acids (lysines).

Surprisingly, both reactions are catalyzed by the same active site of the enzyme. This mechanism was previously unknown and shows how closely the activity of SnCE1 is linked to the metabolic state of the host cell.

Particularly significant, the self-modification determines whether SnCE1 remains active on its own. This is how the bacteria directly adjust their pathogenic effect to the metabolic state of the host cell. The researchers also discovered that enzymes in the host cell influence the bacterial protein by modulating its acetylation state. In turn, this not only changes its activity, but also its location in the cell.

In this way, SnCE1 sometimes migrates to the mitochondria, the cell's powerhouses. When there, the protein initiates the division—a so-called fragmentation —of the mitochondria. Exactly how this happens remains unclear.

Interdisciplinary collaboration for a deeper understanding of infections

The study is the result of close collaboration between research groups at the Faculty of Mathematics and Natural Sciences and University of Medicine Greifswald, as well as external partners at the universities of Würzburg and Cologne. The interdisciplinary collaboration was a key factor in the success of the study and is a good example of how strong networking advances modern research.

The discovery could have long-term implications for medicine. Hospitals are increasingly finding that they can no longer count on standard antibiotics for certain illnesses.

Patients require longer treatment; in some cases, doctors change the medication several times. The Greifswald study describes a mechanism that has received little attention in the past: Bacteria adjust their activity to the metabolic state of human cells, thereby regulating their reproduction in the body.

"Our results show how important the chemical modification of proteins is for adjusting the bacterial virulence factors to the host cell's metabolism," explains lead author Ole Schmöker.

Lammers adds, "SnCE1 can perform various enzymatic reactions catalyzed by the same active site. This enables the protein to get involved directly in cellular processes and adjust its activity according to the condition of the host cell at the same time. A better understanding of such mechanisms should help us decipher basic strategies of bacterial infections.

"In the long term, these findings could contribute to the discovery of new treatment approaches for bacterial pathogens and antimicrobial-resistant bacteria."

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