Achromobacter bacteria seen as new target to fight CF infections
Study: Novel treatments needed to shut down bacteria's molecular weapon
A type of bacteria called Achromobacter, which can cause problematic lung infections in people with cystic fibrosis (CF), uses a molecular weapon — one known as a type 3 secretion system — to induce a powerful inflammatory response during infections, a new study found.
“These bacteria resist the action of multiple antibiotics,” Miguel A. Valvano, PhD, the study’s senior author and a professor of microbiology and infectious diseases at Queen’s University Belfast’s Wellcome-Wolfson Institute for Experimental Medicine (WWIEM), in Northern Ireland, said in a university press release.
“Therefore, infection by these microorganisms is very difficult to treat by conventional therapies, especially in people living with cystic fibrosis or other immunocompromising conditions, such as patients on chemotherapy,” Valvano said, adding, “Until now, how this opportunistic bacterium interacts with the human immune system has been poorly understood.”
The researchers say their findings may help in developing better treatments against infections in people with CF.
Their study, “The Achromobacter type 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes,” was published in Cell Reports.
Investigating the mechanisms underlying Achromobacter bacteria
CF is characterized by thick, sticky mucus that builds up in various organs, including the pancreas, liver, and intestines, but most notably the lungs. This thick mucus provides a fertile breeding ground for bacteria, and people with the inherited disorder are at increased risk of bacterial lung infections.
Commonly found in soil, Achromobacter is a class of bacteria that can cause recurrent lung infections in people with CF. These bacteria often are resistant to antibiotics, making it challenging to treat infections.
“Achromobacter bacteria can cause chronic and potentially severe infections,” Valvano said.
It’s known that Achromobacter bacteria can interact with the body’s immune system to trigger severe inflammatory reactions, but exactly how these bacteria trigger inflammation hasn’t been understood.
Now, Valvano’s team, along with colleagues at WWIEM and the University of Cambridge, in the U.K., conducted a series of experiments aiming to better understand these molecular mechanisms.
The researchers found that Achromobacter bacteria are able to kill macrophages, a type of immune cell that normally helps to fend off bacterial infections.
Specifically, the bacteria can induce an inflammatory form of programmed cell death called pyroptosis in macrophages. “Pyroptosis” comes from Greek words literally meaning “fiery death.”
When a cell undergoes pyroptosis, it releases a set of pro-inflammatory signaling molecules that prompt other immune cells to launch a more powerful inflammatory attack.
The scientists showed that Achromobacter‘s ability to induce pyroptosis in macrophages is dependent upon a bacterial molecular weapon called a type 3 secretion system (T3SS). This needle-like protein complex allows the bacteria to inject proteins into host cells, manipulating host cell function to their benefit before entering the cells.
When the bacteria were modified to lack a T3SS, they were not able to kill macrophages via pyroptosis.
“This study shows that Achromobacter species can interact with human macrophages to induce pyroptosis … in a T3SS-dependent manner,” the researchers wrote.
The results also showed that Achromobacter-induced pyroptosis is mediated by bacteria sensors called NLRC4 and NLRP3 that promote an inflammatory response.
We propose that Achromobacter interactions with [macrophages] are particularly critical to determine infection and inflammation under conditions where the host is partially immunosuppressed, such as in individuals with cystic fibrosis.
Further experiments in mice showed that Achromobacter induced a powerful inflammatory reaction when administered into the lungs, but T3SS-deficient bacteria were not able to induce such a response.
“Together, our data suggest that the T3SS contributes to eliciting an inflammatory response in the lung that causes significant tissue damage and results in more rapid bacterial clearance,” the researchers wrote.
“We propose that Achromobacter interactions with [macrophages] are particularly critical to determine infection and inflammation under conditions where the host is partially immunosuppressed, such as in individuals with cystic fibrosis or other immunocompromising conditions, where Achromobacter species find a favorable niche to colonize and infect,” the team wrote, stressing that more research is needed into type 3 secretion systems.
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