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by Nick Miller
The world is chock-full of wily disease-causing germs – some so smart they elude the best weapons medical science can muster.
Immunologist Joseph Qualls, PhD, is looking for new ways to battle bugs - hoping to outwit and corner the craftiest of microbes.
The research scientist and his colleagues are finding part of the answer may be reasonably simple. It involves harnessing the power of basic biological building blocks, amino acids, to boost specific components of the immune system. The researchers are focusing on two amino acids in particular, L-arginine and L-citrulline.
“Some pathogens are as smart as they are because they have been evading the immune system for thousands of years,” says Qualls, a researcher in the Division of Infectious Diseases. “Our goals involve developing ways to enhance the immune system that the pathogens haven’t encountered before – something they aren’t expecting.”
In the lab, Qualls models infection with mycobacteria, which cause tuberculosis, leprosy, and related illnesses. The deadly respiratory disease associated with active tuberculosis continues to plague us, especially in less developed parts of the world.
He thinks boosting the activity of macrophages – white blood cells that act as sentries for our immune system and our body’s first line of defense – might be the surprise he is looking for.
“The macrophage is a clever cell that is in every tissue of our bodies,” Qualls explains. “It’s continuously on patrol and able to recognize microbes in infected tissue, engulf them, and subsequently kill them. Macrophages exhibit intrinsic antimicrobial functions, yet these functions are enhanced by recruiting and interacting with other cells of the immune system.”
After “phagocytosing,” or enveloping, germs, macrophages depend on an arsenal of microbicidal molecules, including the free radical chemical nitric oxide (NO), to kill the microbes. The macrophages also rely on other immune cells to enhance their germ-killing activity. For instance, NO production does not become fully efficient unless the infected macrophages receive a second signal from interferon-gamma (IFN-g) – a cytokine produced by T cells and natural killer cells.
Following this activation, macrophages produce a burst of NO to attack germs. After the initial burst, however, NO production declines to protect host tissue. Consequently, the macrophages lose a primary weapon.
What if macrophages had a way to continue producing that burst of NO, at least enough to carry on a vigorous battle until the germs were zapped or additional reinforcements arrived? Qualls and his collaborators have research data suggesting this could boost immunity. Their data also suggest this might eventually help make vaccines and antibiotics – in particular those used to treat mycobacterial diseases – more effective.
The scientists studied cell culture and mouse models to find out what causes NO to deplete so rapidly in macrophages after the initial burst. They identified genes and their related proteins (in the form of amino acids and enzymes) that control this process.
A key player in the regulatory process is the amino acid L-arginine, which is fueled by another amino acid, L-citrulline, to produce NO. During the macrophage’s initial burst of NO and other enzyme activity, L-arginine starts to deplete. This slows the production of NO, possibly in an effort to prevent excessive immune response.
Qualls says boosting the macrophage’s production of NO could be especially helpful for people battling poor health and compromised immunity, or in cases of treatment-resistant disease. He expects this could make medicines more effective, recipients healthier, and treatment costs lower.
In laboratory tests, Qualls’ research team has found that using the amino acid L-citrulline as a nutritional supplement kicks off a process that allows mycobacteria-infected macrophages to use L-arginine to produce more NO.
They studied mice infected with mycobacteria. The macrophages of these mice did not express the gene (ASS1) that allows the immune cells to synthesize L-arginine from L-citrulline. As a result, the mice produced less NO and were more susceptible to infection. This supports the idea that boosting macrophage production of NO with supplemental amino acids might help fight infection.
Qualls and his colleagues hope to prove that supplementing L-citrulline is an easy and inexpensive way to boost immunity in people who need it, especially as an additive therapy to existing vaccines and medicines. If it works for macrophages and mycobacterial disease, the next question they hope to answer is whether this or a separate yet still similar approach might work in other components of the immune system, or in other diseases – both infectious and non-infectious.
“We are still years away from these goals, but I am excited by the progress we are making,” Qualls says. “When you consider that the best tuberculosis treatments involve taking antibiotics for six to nine months, imagine the outcome if we could lessen that time by half. This would decrease overall treatment cost, lessen patient burden, and likely increase patient compliance in finishing antibiotic therapy – reducing the development of antibiotic-resistant mycobacteria.”
Dr. Joseph Qualls
Dr. Joseph Qualls and collaborator Dr. Peter Murray at St. Jude Children’s Research Hospital found the answer to fighting antibiotic-resistant microbes might be simpler than we think.
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