This Lung Cell Decides Who Survives COVID
Scientists have discovered that a rare immune cell type in the lungs, called NAMs, plays a crucial role in surviving COVID-19 by keeping the body’s immune response from turning dangerously destructive.
Rather than simply battling the virus, these cells act like peacekeepers, reining in excessive inflammation that can lead to death. Mice with healthy NAMs survived infection, while those without them died—highlighting the potential for new treatments aimed not at boosting immunity, but at controlling it.
NAMs: Rare Lung Cells Key to COVID-19 Survival
A newly published study has identified a rare type of lung cell as crucial for surviving COVID-19.
Researchers at NYU Langone Health found that a specific class of immune cells, called nerve and airway-associated interstitial macrophages, or NAMs, plays a key role in controlling lung inflammation during SARS-CoV-2 infection. These cells appear to prevent the immune system’s initial response from becoming dangerously excessive. Macrophages like NAMs are immune system “first responders” known for engulfing viruses and infected cells.
The study, published today (April 25) in the journal Immunity, suggests a shift in treatment strategy: rather than boosting the immune attack, it may be more effective to focus on controlling that response, an approach known as “disease tolerance.”
Study Results Highlight NAMs’ Protective Role
In experiments with mice infected by SARS-CoV-2, those lacking NAMs experienced uncontrolled viral spread, severe inflammation, significant weight loss, and ultimately, death. In contrast, mice with functioning NAMs had less viral spread, milder inflammation, minimal weight loss, and all survived. The researchers also found that NAMs limit the production of pro-inflammatory signaling proteins, which helps reduce tissue damage. Notably, NAMs increase in number over time, unlike many other immune cells that tend to decline as infection progresses.
“Our findings underscore the critical role of nerve and airway-associated interstitial macrophages in the lungs in regulating the inflammatory response during SARS-CoV-2 infection,” said study co-lead investigator Payal Damani-Yokota, PhD, a postdoctoral fellow at NYU Grossman School of Medicine. “The absence of these NAM immune cells leads to an exaggerated inflammatory response against the COVID-19 virus, cell death, and increased viral spread.”
NAMs Control Inflammation via IFNAR Protein
The results also showed that NAMs rely on a protein called type 1 interferon receptor, or IFNAR, to have their effect on the immune response to SARS-CoV-2. When the team genetically engineered NAMS so that they could no longer produce IFNAR – and so no longer respond to the immune signaling protein interferon – the cells could not tamp down inflammation. In this scenario, the same percentage of mice died as did when NAMS were depleted (100%).
Human Tissue Confirms Mouse Findings
Further testing in lung tissue from patients who had been intubated due to severe SARS-CoV-2 infection (some survived, and others did not) showed decreased activity in NAM-related genes and heightened inflammation in those who died. This confirmed for the researchers that their NAM findings in mice mimicked what occurs during infection in humans.
“Our study shows that nerve and airway-associated interstitial macrophages in the lungs, or NAMs, rely on type 1 interferon signaling for their expansion and normal functioning during SARS-CoV-2 infection,” said senior study investigator Kamal Khanna, PhD, an associate professor in the Department of Microbiology at NYU Grossman School of Medicine.
Previous NAM Research Set the Stage
The same NYU Langone team discovered in 2020 that a small fraction (less than 5%) of lung macrophages acted differently during infection with the influenza virus by not attacking it. Instead, they found that these cells, which they named NAMs, tamped down the initial immune response and prevented prolonged inflammation from causing damage to lung tissue as it attempted to heal. This led the team to suspect that NAMs might play a similar role in COVID-19.
“The new work unveils nerve and airway-associated interstitial macrophages as key players in the choreography of recovery—poised to silence the alarms of inflammation and restore calm, even in the midst of interferon’s call to amplify the immune response,” said Benjamin tenOever, PhD, the Jan T. Vilcek Professor of Molecular Pathogenesis, and chair, of the Department of Microbiology at NYU Langone.
Future Treatment Pathways and Broader Implications
Moving forward, the researchers plan to study NAM pathways to determine how the macrophage subset moderates inflammation. Specifically, the team plans to investigate type 1 interferon signaling and how it triggers NAM growth in response to SARS-CoV-2 infection.
If further experiments prove successful, Khanna says his team’s findings could be used to develop treatment strategies that harness IFNAR signaling to promote disease tolerance. This approach may apply to COVID-19 and other respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.
Reference: “Nerve- and airway-associated interstitial macrophages mitigate SARS-CoV-2 pathogenesis via type I interferon signaling” by Stephen T. Yeung, Payal Damani-Yokota, Sara A. Thannickal, Eric Bartnicki, Eduardo D. Bernier, Clea R. Barnett, Camille Khairallah, Ralf Duerr, Maria G. Noval, Leopoldo N. Segal, Kenneth A. Stapleford and Kamal M. Khanna, 25 April 2025, Immunity.
Funding support for this study was provided by National Institutes of Health grants P30CA016087, R01AI143861, R01AI162774, R33GM147800, U01AG088351, F32HL154598, and 5T3-A1100853. Additional funding support came from American Lung Association grant #917496 and American Heart Association grant 19-A0-00-1003686.
In addition to Damani-Yokota and Khanna, other NYU Langone researchers involved in this study include co-lead investigator Stephen Yeung, now at Weill Cornell, New York City, and co-investigators Sara Thannickal, Eric Bartnicki, Eduardo Bernier, Clea Barnett, Camille Khairallah, Ralf Duerr, Maria Noval, Leopoldo Segal, and Kenneth Stapleford.