September 2026

PULMONARY

EXPERIMENTAL DRUG MAY DISRUPT IMMUNE CIRCUITS IN PNEUMONIA

Featuring: Scott Budinger, MD

A drug that blocks calcium release-activated calcium (CRAC) channels may help interrupt harmful immune cell interactions that drive severe viral pneumonia, according to a new study published in The Journal of Clinical Investigation.
The findings provide new insight into how the experimental drug zegocractin works and may inform future precision medicine approaches to treating pneumonia, says the study’s senior author G. R. Scott Budinger, MD.

​Building on Nature-Published COVID-19 Findings
The study grew out of observations made during the COVID-19 pandemic, Dr. Budinger says. “During the pandemic, we published a paper in Nature that showed that the persistent inflammation that we were seeing in patients with COVID-19 was in part driven by an interaction between monocyte-derived macrophages that were in the alveolar space and T-cells,” he explains. “In light of those findings, inhibiting T-cell activation seemed like a really good idea.”

In the most recent study, investigators administered zegocractin to patients with severe COVID-19 pneumonia on mechanical ventilation in the ICU. Zegocractin inhibits CRAC channels. Although other studies of the drug showed a reduction in 30-day mortality in COVID-19 patients, the mechanisms behind this remained unclear.
Because participants were receiving mechanical ventilation, investigators were able to collect bronchoalveolar lavage samples from the lungs and measure both drug levels and biological responses at the site of infection. 
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Inhibiting Inflammatory Circuits
Although the study enrolled a relatively small number of patients and was not designed to measure clinical outcomes, the investigators found that zegocractin dampened inflammatory circuits between T-cells and macrophages, two cell types implicated in severe pneumonia. Lab experiments, including RNA sequencing, further suggested that the drug primarily acted on T-cells, reducing signals that can activate inflammatory macrophages.

“The findings that we had were consistent with the hypothesis that this drug was inhibiting those macrophage T-cell circuits,” Budinger said. “Our findings in Nature were subsequently confirmed by other groups, so this is probably a robust mechanism.”

Takeaways for the Medicine of Tomorrow
Dr. Budinger says the implications may extend beyond COVID-19, like offering a therapy option for patients with viral pneumonia. The findings underscore the need for more personalized approaches to treating infectious diseases. Future studies will aim to identify which patients are most likely to benefit from therapies targeting specific immune pathways.

“I think it highlights the importance of very deep phenotyping of our pneumonia patients before we actually start to give drugs that target their immune response,” Dr. Budinger adds. He emphasizes that small trials with deep molecular phenotyping are the future of precision medicine therapies.
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​Alexander Misharin, MD, PhD, was corresponding author of the study. Benjamin Singer, MD, and Richard Wunderink, MD, were equally contributing senior co-authors. The study was supported by NIH grants K23HL169815, a Parker B. Francis Opportunity Award, and an American Thoracic Society Unrestricted Grant. 
 
​Read more on the Northwestern University Feinberg School of Medicine News Center.
Scott Budinger, MD, the Ernest S. Bazley Professor of Airway Diseases and chief of Pulmonary and Critical Care in the Department of Medicine, was senior author of the study.
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