Findings promote "disease tolerance" approach
instead of attacking the virus
NEW
YORK, April 25, 2025 /PRNewswire/ -- A rare cell
type in the lungs is essential to survival from the COVID-19 virus,
a new study shows.
Experiments in mice infected with the SARS-CoV-2 virus revealed
that the immune cell class in question, called nerve and
airway-associated interstitial macrophages, or NAMs, may keep the
human immune system's initial counterattack on the virus (lung
inflammation) from spiraling out of control to endanger patients.
Macrophages are known to be the first responders to infection, as
large immune cells capable of devouring invading viruses and the
cells they infect.
Led by researchers at NYU Langone Health, the study shifts the
focus for treating the disease away from strengthening the immune
system attack on the virus and toward better restraint of the
immune response, what researchers call "disease tolerance."
Publishing in the journal Immunity online April 25, the researchers found in NAM-depleted
mice infected with SARS-CoV-2 that viral infection spread,
heightened inflammation and weight loss, and caused all of them to
die. By contrast, infected mice with intact NAMs showed limited
viral spread, weight loss, and inflammation. All the animals in
this group survived infection. NAMs were also shown to restrict the
production of highly pro-inflammatory signaling proteins to prevent
tissue damage. A unique feature of NAMs, the researchers say, is
that their numbers grow over time, where most immune cell sets
start to taper off.
"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."
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%).
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, 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.
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.
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.
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.
About NYU Langone Health
NYU Langone Health
is a fully integrated health system that consistently achieves the
best patient outcomes through a rigorous focus on quality that has
resulted in some of the lowest mortality rates in the
nation. Vizient Inc. has ranked NYU Langone
No. 1 out of 115 comprehensive academic medical centers
across the nation for three years in a row, and U.S. News &
World Report recently placed nine of its clinical specialties among
the top five in the nation. NYU Langone offers a
comprehensive range of medical services with one high standard of
care across seven inpatient locations, its Perlmutter
Cancer Center, and more than 320 outpatient locations in the
New York area and Florida. With $14.2
billion in revenue this year, the system also includes two
tuition-free medical schools, in Manhattan and on Long Island, and a vast research
enterprise.
Media Inquiries
David
March
Phone: 212-404-3528
David.March@NYULangone.org
View original content to download
multimedia:https://www.prnewswire.com/news-releases/lung-immune-cell-type-quietly-controls-inflammation-in-covid-19-302436751.html
SOURCE NYU Langone Health System
