Nerve- and Airway-Associated Interstitial Macrophages Mitigate SARS-CoV-2 Pathogenesis via Type I Interferon Signaling

Infectious Diseases Life Sciences Respiratory System Medicine Immunology
SARS-CoV-2 Type I Interferon Macrophages Inflammation Viral Infection

1. Academic Background

The COVID-19 pandemic has highlighted the importance of immunoregulatory mechanisms in respiratory viral infections. Despite vaccine advancements, the rapid mutation of SARS-CoV-2 continues to threaten public health. Studies indicate that severe COVID-19 cases are often associated with dysregulated immune responses rather than direct viral load. In this context, the role of tissue-resident macrophages (RTMs) in maintaining pulmonary immune balance has emerged as a critical scientific question.

The lung harbors multiple macrophage subsets, among which nerve- and airway-associated macrophages (NAMs) are a recently identified subpopulation. Previous research demonstrated NAMs’ immunoregulatory functions during influenza infection, but their mechanistic role in SARS-CoV-2 infection remained unclear. This study elucidates a novel mechanism by which NAMs regulate SARS-CoV-2 infection through type I interferon (IFNAR) signaling.

2. Publication Details

This study was conducted by Stephen T. Yeung, Payal Damani-Yokota, and colleagues from the Department of Microbiology at NYU Grossman School of Medicine, with corresponding author Prof. Kamal M. Khanna. Collaborators included researchers from Pulmonary & Critical Care Medicine, Vaccine Center, and other departments. The paper was published on May 13, 2025, in Immunity (Impact Factor: 43.474), DOI:10.1016/j.immuni.2025.04.001.

3. Methodology and Key Findings

1. Experimental Design

a) Animal Models

  • NAM-depletion model: Generated NAM-DTR (diphtheria toxin receptor) mice by crossing CD169-Cre with B6N.129P2-Cx4cr1tm3(DTR)Litt/J mice for selective NAM ablation
  • Conditional knockout: Developed CD169-Ifnar CKO mice (CD169cre/wtIfnarflox/flox) to delete IFNAR specifically in CD169+ macrophages

b) Viral Infection

  • Intranasal infection with mouse-adapted SARS-CoV-2 (MA-10, 1,000 PFU)
  • Experimental groups: Wild-type (WT), NAM-DTR, and Ifnar-CKO (n=4-5/group)
  • Outcomes: Survival rate, weight loss, lung pathology (2⁄5 days post-infection, dpi)

c) Multimodal Analysis

  • Flow cytometry: Quantified immune subsets (CD45+Ly6G+ neutrophils, CD169+CD11c+ alveolar macrophages)
  • Cytokine profiling: Luminex assay for 28 inflammatory factors (IFN-α/β/γ, IL-1β, IL-6, etc.)
  • Confocal microscopy: 3D reconstruction of viral distribution (anti-SARS-Spike S2 staining)
  • scRNA-seq: Analyzed human lung NAM-like macrophages from public datasets

2. Major Discoveries

a) NAMs Are Essential for Survival

  • Mortality: 100% death in NAM-DTR mice by 4-5 dpi (p<0.0001) vs. 100% survival in WT
  • Pathology: NAM depletion caused severe acute lung injury, including alveolar wall thickening (3.2±0.5μm vs. WT 1.8±0.3μm) and neutrophil infiltration (5.6×10⁵ vs. WT 2.1×10⁵ cells)

b) Viral Containment Mechanism

  • Spatial restriction: In WT, virus was confined to large airways (12.3% S2+ area at 2dpi) vs. widespread dissemination in NAM-DTR (41.7%)
  • Subset susceptibility: Alveolar macrophages (AMs) were infected (18.5% positivity), whereas NAMs remained virus-free

c) Inflammatory Regulation

  • Cytokine storm: NAM-DTR showed dramatic increases at 5dpi:
    • IL-6: 1,842 pg/mL vs. WT 326 pg/mL
    • MCP-1: 38,765 pg/mL vs. WT 1,024 pg/mL
  • Neutrophil activation: NETosis markers (H3+ staining) increased 4.3-fold

d) IFNAR-Dependent Mechanism

  • Genetic validation: Ifnar-CKO mice fully phenocopied NAM-DTR (100% lethality)
  • Proliferation control: NAMs expanded 2.8-fold in WT but not in Ifnar-CKO (Ki-67+ cells: 34.2% vs. 8.7%)

3. Clinical Relevance

  • scRNA-seq: Identified human NAM-like macrophages expressing FOLR2, F13A1, and GAS6
  • Patient data: Deceased COVID-19 patients showed 2.1-3.8-fold lower NAM-related gene expression (p<0.01) and elevated BALF cytokines (IL-6, MCP-1)

4. Research Impact and Innovations

1. Scientific Significance

  • First demonstration of NAMs mediating disease tolerance via IFNAR signaling
  • Reveals subset-specific responses: NAMs require IFNAR for expansion, whereas AMs do not

2. Clinical Implications

  • Proposes NAM-related gene signatures as biomarkers for severe COVID-19
  • Suggests targeting the NAM-IFNAR axis as a therapeutic strategy

3. Methodological Advances

  • Development of CD169-Ifnar CKO mice
  • Multiscale analytical framework (single-cell to whole-organ pathology)

5. Highlights

  1. Conceptual breakthrough: Proposes “spatiotemporal immunoregulation by macrophage subsets” to explain how localized NAMs exert global protection
  2. Technical integration: Combines genetic models (DTR/CKO) with clinical omics (scRNA-seq, proteomics)
  3. Translational value: Identifies conserved NAM signature genes for diagnostic applications

6. Future Directions

Authors outline remaining questions:
- Specific immunoregulatory molecules secreted by NAMs
- Downstream IFNAR effectors (e.g., ISG15, IFITM3)
- NAM roles in other respiratory viruses (RSV, MERS-CoV)

This study provides a paradigm shift in understanding tissue-resident macrophage heterogeneity, hailed by reviewers as a “landmark in respiratory immunology.”