Innovative research led by a uOttawa Faculty of Medicine professor whose lab focuses on mechanisms that maintain a healthy immune system has discovered that a gene best known for increasing the risk of Parkinson's disease may also give the body an edge in fighting dangerous infections.
The findings suggest that a well-studied mutation in the LRRK2 gene — whose mutated form is one of the most common genetic causes of Parkinson's — actually strengthens the ability of key immune cells to destroy killer bacteria.
The work recently published in the journal Cellular & Molecular Immunology could open new possibilities for eventually developing therapies that strike a careful balance—strengthening protection against infection while minimizing the harmful effects of chronic inflammation.
Lead investigator Dr. Subash Sad says it also highlights a delicate balancing act: while a stronger immune response can improve protection against infection, it can also increase the risk of tissue damage if left unchecked.
"Mutations in the LRRK2 gene are frequent in chronic inflammatory conditions, but their role in these diseases is not clear," says Dr. Sad, professor in the Faculty's Department of Biochemistry, Microbiology and Immunology. "We have shown that LRRK2 is abundantly expressed in immune cells in the bone marrow, where many immune cells are generated."
Mutation may supercharge bacteria-fighting cells
The team of collaborators looked at the impact of the mutation on neutrophils—the body's rapid-response white blood cells.
These cells engulf invading microbes and destroy them using several antimicrobial weapons, including reactive oxygen species (ROS), highly reactive molecules that kill bacteria trapped inside immune cells.
Here's what they found: Neutrophils carrying the mutation produce significantly more reactive oxygen species, making them more effective at eliminating intracellular bacteria. The team traced this enhanced antibacterial activity to a molecular system responsible for generating reactive oxygen species.
An evolutionary arms race
The findings also provide new insights into the never-ending evolutionary battle between pathogens and the immune system.
The research team investigated Salmonella Typhimurium, a common bacterium capable of causing severe illness. They found that the pathogen produces a protein that effectively reduces reactive oxygen species production and helps the bacteria survive inside immune cells.
This finding illustrates the arms race between pathogens and their hosts, with bacteria evolving ways to evade destruction while the immune system develops increasingly effective defenses.
Dr. Sad says the genetic mutation the team focused on appears to help the body clear certain bacterial infections more effectively. This suggests the mutation may have provided an evolutionary advantage by strengthening the body's ability to fight infections.
"It is therefore conceivable that these mutations may be preserved as long as we continue to face the threat of infections," he says.
Toward better-targeted immune therapies
The new research underscores a biological double-edged sword. While increased reactive oxygen species help eliminate dangerous bacteria during acute infections, excessive or prolonged production can damage healthy tissues and contribute to chronic inflammation.
"Balance is the key operative word for the immune system," Dr. Sad says. "Too much or too little response can be catastrophic."
That balance could prove important in better understanding diseases already linked to LRRK2, including Parkinson's disease and chronic inflammatory disorders such as Crohn's disease and leprosy.
The findings point toward potential new treatment strategies. Rather than simply increasing or suppressing immune activity, future therapies may aim to fine-tune it—preserving the body's ability to eliminate bacteria while preventing excessive inflammation.
The study's significance was echoed during peer review. As one reviewer noted: "In addition to insights into LRRK2's contribution to the pathogenesis of immune diseases, the work also offers implications for the mechanisms of Parkinson's disease development driven by the G2019S mutation, making it an impactful paper for a broad readership."
Looking ahead, Dr. Sad says the research team plans to investigate how different LRRK2 mutations influence immunity and disease progression, while also exploring whether infections contribute to long-term changes in brain regions affected by Parkinson's.
