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Research

Proton-Activated Chloride Channel 1 Acts as a Crucial Defense Mechanism Against Bacterial Sepsis

Sepsis is a life-threatening emergency caused by the body’s response to infection, leading to potential tissue damage, organ failure and death. An estimated 50 million annual cases of sepsis occur worldwide with mortality rates of 20-50% and may account for up to half of U.S. hospital deaths. It is considered to be the most expensive condition affecting the country’s healthcare system.

Pneumonia is a major risk factor for sepsis, causing approximately 50% of all cases and is itself a leading cause of death in children under five and in the elderly. Unfortunately, antibiotic resistance has been increasing amongst bacterial pathogens and infection-associated mortality in the U.S has not significantly improved since the widespread use of antibiotics. Treatment of bacterial infections is further complicated by limited diagnostic capabilities because the exact infectious microbe remains unidentified in a majority of bacterial sepsis cases.

Discovering the fundamental mechanisms our immune cells use to fight infection is key to developing new therapies that protect people and improve health worldwide, especially as antibiotic resistance continues to rise.

Markus Bosmann, MD, associate professor of medicine, pathology & laboratory medicine

In a new study, researchers from Boston University Chobanian & Avedisian School of Medicine have discovered that an acid-sensitive chloride channel, called PACC1, plays an important role in defending the body against bacterial infections and sepsis. In macrophages, the immune cells that “eat” invading bacteria, PACC1 helps control the phagolysosome, the compartment that digests bacteria. Without PACC1, this process does not work efficiently. This is the first time PACC1’s role in immune defense has been identified and described.

“Chloride channels like PACC1 are important for many bodily functions, and problems with them can cause diseases—like how mutations in Cystic Fibrosis Transmembrane Conductance Regulator cause cystic fibrosis. Our data suggest that mutations in PACC1 in humans may lead to abnormal immune cell function and higher risk of sepsis, a life-threatening infection, ”explains corresponding author Markus Bosmann, MD, associate professor of medicine, pathology & laboratory medicine at the school.

The researchers studied macrophages in the lab that either had PACC1 or had the PACC1 gene removed. When they exposed these cells to bacteria, the macrophages lacking PACC1 were less able to acidify (lowering its pH level below 7) their phagolysosomes and were worse at “eating” and killing bacteria. Similar to stomach acid helping to digest food, the acidic environment inside the phagolysosome is critical for breaking down bacteria.

According to the researchers, this study highlights that even small molecular components inside immune cells can have major effects on the body’s ability to fight infection. “Discovering the fundamental mechanisms our immune cells use to fight infection is key to developing new therapies that protect people and improve health worldwide, especially as antibiotic resistance continues to rise. Therapies that increase PACC1 activity or improve its function could someday help treat or prevent serious infections,” adds Bosmann.

These findings appear online in the journal Proceedings of the National Academy of Sciences (PNAS).