Defects in Mitochondria May Sustain Burkholderia Cenocepacia Infections in CF

Specific immune cells called macrophages in cystic fibrosis (CF) are unable to kill the bacteria Burkholderia cenocepacia due to impairments in mitochondria, the cell’s powerhouses, a new mouse study says.

The finding suggests that boosting mitochondria function could help resolve chronic infection in CF.

The study “Defective immunometabolism pathways in cystic fibrosis macrophages” was published in the Journal of Cystic Fibrosis.

Macrophages, immune cells specialized in the detection and destruction of bacteria and other harmful agents, have been shown to contribute to CF.

Previous research found that the function of macrophages in a CF mouse model was impaired. Specifically, macrophages had an impairment in their ability to undergo autophagy, a natural cleaning system used by cells to get rid of damaged components and pathogens.

This made the cells unable to clear infection by the Burkholderia cenocepacia (B. cenocepacia), a type of opportunistic bacteria that can cause lower respiratory infections in patients with CF and can be resistant to antibiotics.

Mitochondria — cells’ energy source — are particularly important for the proper function of macrophages. Upon an infection, healthy macrophages use their mitochondria to produce mitochondrial reactive oxygen species (mROS) that trigger inflammation and destroy bacteria.

Previous studies suggested that mitochondria are defective in CF, but whether this plays a role in macrophages function remains unknown.

To answer this question, researchers at the College of Medicine at The Ohio State University studied macrophages from healthy mice and from a CF mouse model with the F508del mutation, the most common mutation found in the CFTR gene (the defective gene causing CF).

Specifically, researchers looked at how the mitochondria metabolism affected macrophages’ response to B. cenocepacia bacterial infection.

First, they observed that mitochondria from CF macrophages worked poorly compared to mitochondria in healthy macrophages.

Two indicators of mitochondrial working capacity, called maximal respiration and spare respiratory capacity, were significantly impaired in CF macrophages. This meant that when called into action, their mitochondria would have more difficulty trying to respond to an increased demand for energy.

Indeed, this was observed when macrophages were infected with B. cenocepacia, as mitochondria in macrophages from CF were less capable of responding to an increased energy demand following infection.

The oxygen consumption rate, another measure of mitochondria’s health, also was reduced in CF macrophages compared to healthy cells.

Next, researchers looked at how B. cenocepacia affected the mitochondria of CF macrophages. Six hours after infection, the team observed that the mitochondria were smaller, less elongated and had lower interconnectivity scores, all signs suggesting that infection triggered the fragmentation of CF mitochondria.

At a metabolic level researchers saw that, when infected, CF macrophages had a higher mitochondrial membrane potential compared to healthy macrophages. This meant that the metabolism in the CF macrophages changed and was more glycolysis-dependent, a more inefficient way for mitochondria to produce energy.

Before infection, no significant differences in mitochondrial ROS production were found between healthy and CF macrophages. After infection, both macrophages increased their ROS levels. Yet, previous work had demonstrated that CF macrophages accumulated more bacteria due to a defective autophagy mechanism, which could mask defects in mitochondrial ROS production.

To untangle these effects, researchers decided to block bacteria replication and measure mitochondrial ROS levels.

The results showed that two hours after infection, CF macrophages slowed down mitochondrial ROS production and by eight hours there was a significant decrease in ROS compared to healthy macrophages.

Overall, these findings suggested that mitochondria impairments affect the ability of CF macrophages to respond to infections. The team suggested that “correcting mitochondrial defects may improve CF macrophage function.”

“Future work building off of our current findings will help to identify mitochondria-based therapeutic targets that will contribute to resolving the chronic infection and inflammation characterizing CF,” the team added.