Naturally occurring carbon monoxide (CO) is essential for macrophages’ surveillance and subsequent attack on foreign intruders or pathogens, according to investigators at Beth Israel Deaconess Medical Center (BIDMC).

In a study appearing in the November issue of The Journal of Clinical Investigation (JCI), the researchers describe a scenario in which CO conducts reconnaissance for immune cells, working to detect the presence of bacteria and subsequently instigating a series of maneuvers that enable the immune cells to unleash their attack on the microbes.

The new findings support the possibility that in the future, small, non-toxic doses of carbon monoxide could be used therapeutically to provide the immune system with an infection-fighting advantage and to potentially complement the use of antibiotics as the standard of care for bacterial infections.

“In battling bacteria, the immune system conducts a two-step signaling process. This ensures that immune cells become fully activated only when confronted with live bacteria; when presented with bacterial fragments, such as the lipid polysaccharides present on bacteria’s outer walls, immune cells become only mildly stimulated,” ”¬†says senior author Leo E. Otterbein, PhD, an investigator in the Division of Transplantation in BIDMC’s Department of Surgery and Associate Professor of Surgery at Harvard Medical School (HMS).

“This distinction conserves energy and helps the immune cells to maintain an efficient defense system. We now see that CO plays a critical role in the execution of this two-step process, enabling the immune cells to successfully carry out their attack.”

Otterbein has been studying carbon monoxide for more than 12 years and his novel studies have revealed promising therapeutic applications for the gas, including treatment of pulmonary hypertension, prevention of organ rejection following transplantation, reduction of vascular restenosis and, most recently, shrinkage of cancerous tumors. Clinical trials to test inhaled CO for the treatment of lung disease, intestinal dysfunction and organ transplantation are currently underway.

Subsequent experiments in cell culture and confirmed in animal models revealed the mechanisms underlying the immune cells’ two-step process.

Led by first author Barbara Wegiel, PhD, an investigator in BIDMC’s Division of Transplantation and Assistant Professor of Surgery at HMS, t

“It turns out that the first signal – which puts white blood cells on alert without engaging them to become fully activated – causes HO-1 to generate CO inside the cell,” says Barbara Wegiel, PhD, an investigator in BIDMC’s Division of Transplantation and Assistant Professor of Surgery at HMS.

She added that the macrophages next send the CO outside the cell, in the form of a gas, to determine if a live bacteria actually exists in the region. If no active bacteria is present, the CO dissipates. But if dangerous microbes are lurking, the CO takes on a new responsibility and attaches itself to specific locations on the bacteria.

“When CO comes in contact with bacteria, it adheres to the protein complexes that compel the bacteria to uncharacteristically release adenosine triphosphate or ATP, a powerful signaling molecule involved in energy production for which specific receptors exist on the surface of the macrophages,” says Otterbein. And this, he explains, serves as the second signal to alert the immune cells to take action. “This giant burst of ATP leads to the macrophages themselves becoming super activated, but also leads to their calling in greater numbers of the hosts’ white blood cell forces because now it’s clear there’s a real infection to be fought.”

The discovery unveils a new concept and offers a new avenue for the development of therapies to complement or potentially reduce the need for antibiotics and thus limit the development of antibiotic resistance, say the authors.