Stronger but Fewer Neutrophils Could Help Battle Superbugs
The significance of developing host-modulating personalized therapies to counteract the growing threat of antimicrobial resistance is well-recognized because such resistance cannot be overcome using microbe-centered strategies alone.
Therefore, an ideal antimicrobial treatment would enhance bactericidal activity while preventing neutrophilic inflammation, which can induce tissue damage.
Researchers at Boston Children’s Hospital now describe an approach that can do both- enhanced bacterial killing with reduced lung damage.
Antibiotic resistance is a growing threat in bacterial pneumonia. While immune-stimulating treatments can help the body kill the bacteria, they can also cause inflammation that damages and weakens lung tissue. “The question is, when we have pneumonia, do we want to enhance neutrophil function or suppress it? It’s very tricky,” says Hongbo (Robert) Luo, PhD, a researcher in the Department of Laboratory Medicine at Boston Children’s Hospital and senior investigator on the study.
His team, along with collaborators at the Chinese Academy of Medical Sciences and Peking Union Medical College in China, investigated the role of the enzyme IP6K, which has recently been shown to inhibit signalling by another molecule in neutrophils called PIP3. When IP6K is inhibited in a mouse model, PIP3 becomes elevated and neutrophils become more active, killing more bacteria
and living longer—”like ‘super’ neutrophils.When the team deleted the IP6K1 gene in the mice, they saw enhanced bacterial killing by neutrophils, which more actively engulfed bacteria and killed them with toxic compounds.
When the researchers used TNP, an IP6K inhibitor drug, instead of genetic manipulation, results were the same. The team also found that the effect was occurring through blood platelets, which produce a chemical regulator known as polyphosphate that makes neutrophils more active and apt to migrate.
In addition, Boston Children’s Transfusion Medicine group, where Dr. Luo’s lab is based, is interested in pursuing IP6K inhibition in cancer patients, who often have severely reduced neutrophil counts that put them at high risk for infection. “We could try transfusing neutrophils—treated with TNP to enhance neutrophil function, but leaving platelets untreated so that neutrophil recruitment wouldn’t be inhibited,” Dr. Luo says.
