Scientists have shown that the bacterial pathogen Legionella pneumophila has developed a specific strategy to target host cell mitochondria, the organelles in charge of cellular bioenergetics. Their study provides information on how a pathogen manipulates the cellular metabolism to replicate intracellularly, and proposes a new concept of protection of host cells from Legionella-induced mitochondrial changes in order to fight infection.
Intracellular pathogens adopt various strategies to circumvent the defences of host cells and to proliferate intracellularly. One specific strategy is to target host organelles like the mitochondria. Mitochondria are well-defined cytoplasmic organelles that conduct many cellular metabolic functions. Mitochondria supply energy to the cell, and are thus referred to as the 'power house' of the cell. Some bacteria, including Legionella pneumophila, are able to alter mitochondrial functions to the pathogens advantage.
L. pneumophila is a bacterial pathogen that causes legionellosis—a disease characterized by acute pulmonary infection, which is often fatal when not treated promptly. In France, between 1200 and 1500 cases are identified each year, with mortality rates ranging from 5 to 15 percent.
Researchers from the Institut Pasteur, CNRS and Inserm, in collaboration with a team from Switzerland, have discovered a previously unknown mechanism by which L. pneumophila targets mitochondria to modulate mitochondrial dynamics and thereby impairs mitochondrial respiration, which in turn leads to a change in the cellular metabolism. These metabolic changes in the host cell favour bacterial replication. Thus, the rewiring of cellular bioenergetics to create a replication permissive niche in host cells is a core virulence strategy of L. pneumophila.
The researchers found that L. pneumophila establishes transient, highly dynamic contacts with host mitochondria and secretes an enzyme called MitF that modifies the shape of the mitochondria by inducing DNM1L-dependent mitochondrial fragmentation. Surprisingly, L. pneumophila-induced mitochondrial fragmentation is independent of cell death and ultimately impairs mitochondrial respiration, whereas cellular glycolysis is increased. Thus, the bacterial-induced changes in mitochondrial dynamics promote a Warburg-like phenotype (which is characteristic of cancerous cells) in the infected cell that favours bacterial replication.
Researchers theorized that protecting host cells from Legionella-induced mitochondrial changes may help to fight infection. Indeed, pre-treating of human cells with a compound that inhibits changes in mitochondrial morphology protects the host cell from Legionella-induced changes of mitochondria and restricts bacterial infection of human cells.
Carmen Buchrieser, head of the Biology of the intracellular bacteria research unit at the Institut Pasteur and researcher at CNRS, says, "This is an important discovery as our results showcase a key strategy used by L. pneumophilia for intracellular replication. By targeting mitochondria, the bacterium ensures that the host cell will be permissive to its replication. It is therefore essential that researchers also focus their studies on metabolic changes caused by pathogenic bacteria in order to develop new therapeutic strategies against legionellosis and other diseases linked to intracellular bacteria."
This work sheds new light on how a pathogen shapes host metabolic responses during infection of human cells and shows that metabolic changes in the host cell are instrumental for pathogenic replication in human cells and thus to cause disease. It also proposes a new concept, which is to treat infections by inhibiting pathogen-induced metabolic changes.
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Pedro Escoll et al, Legionella pneumophila Modulates Mitochondrial Dynamics to Trigger Metabolic Repurposing of Infected Macrophages, Cell Host & Microbe (2017). DOI: 10.1016/j.chom.2017.07.020