Drug-Resistant Pneumonia Sensitive to Neutrophil Modulation

An increasing problem in cases of bacterial pneumonia is antibiotic resistance. While immune-stimulating therapies can help the body kill the bacteria, they can also cause inflammation that damages and weakens lung tissue.

In a paper (“Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia”) in Science Translational Medicine, researchers at Boston Children’s Hospital describe a technique that provides enhanced bacterial killing while reducing lung damage.

“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,” write the investigators. “Immune host defenses must be finely controlled during infection to balance pathogen clearance with unwanted inflammation-induced tissue damage. Thus, an ideal antimicrobial treatment would enhance bactericidal activity while preventing neutrophilic inflammation, which can induce tissue damage. We report that disrupting the inositol hexakisphosphate kinase 1 (Ip6k1) gene or pharmacologically inhibiting IP6K1 activity using the specific inhibitor TNP [N2-(m-(trifluoromethyl)benzyl) N6-(p-nitrobenzyl)purine] efficiently and effectively enhanced host bacterial killing but reduced pulmonary neutrophil accumulation, minimizing the lung damage caused by both Gram-positive and Gram-negative bacterial pneumonia.”

“IP6K1-mediated inorganic polyphosphate (polyP) production by platelets was essential for infection-induced neutrophil-platelet aggregate (NPA) formation and facilitated neutrophil accumulation in alveolar spaces during bacterial pneumonia. IP6K1 inhibition reduced serum polyP levels, which regulated NPAs by triggering the bradykinin pathway and bradykinin-mediated neutrophil activation,” the investigators continue. “Thus, we identified a mechanism that enhances host defenses while simultaneously suppressing neutrophil-mediated pulmonary damage in bacterial pneumonia. IP6K1 is, therefore, a legitimate therapeutic target for such disease.”

When the immune system sees a bacterial infection, it triggers an influx of neutrophils at the infection site. Neutrophils can kill the bacteria, but they also cause harm by releasing inflammatory compounds that damage the lung’s air sacs.

“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, Ph.D., a researcher in the Department of Laboratory Medicine at Boston Children’s Hospital and senior investigator on the study.

Dr. Luo’s lab has long been studying the enzyme IP6K, and recently showed that it inhibits signaling 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,” says Dr. Luo.

His team, along with collaborators at the Chinese Academy of Medical Sciences and Peking Union Medical College in China, decided to further investigate IP6K1’s role in neutrophil function in a mouse model of bacterial pneumonia. 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.

But the researchers also saw reduced neutrophil accumulation in the lungs’ air spaces and reduced lung damage. “This was a surprise,” says Dr. Luo. “The exciting thing is that bacterial killing is high, and tissue damage is low.”

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.

“When we inhibit IP6K, platelets make less polyphosphate, reducing neutrophil recruitment,” explains Dr. Luo. “But when the neutrophils get there, they kill bacteria more. We have a treatment that can enhance neutrophils’ bacterial killing activity, but their recruitment is controlled, so we have better outcomes.”

Dr. Luo cautions that TNP has never been tested as a potential drug in humans. But he thinks the study findings may have implications not just for bacterial pneumonia, but for other infections that involve neutrophils.

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.