Opposing Association of Lung Neutrophils and PD‐L1+ Monocytes in Age‐Related Severity of SARS‐CoV‐2 Infection

DOI record: { "DOI": "10.1111/acel.70588", "ISSN": [ "1474-9718", "1474-9726" ], "URL": "http://dx.doi.org/10.1111/acel.70588", "abstract": "<jats:title>ABSTRACT</jats:title>\n <jats:p>Advanced age is a major determinant of adverse outcomes during acute infections, yet the immunological mechanisms by which aging alters immune regulation and shapes disease trajectories remain poorly understood. Using SARS‐CoV‐2 infection as a model of acute viral challenge, we investigated how aging alters myeloid responses in the lungs. Across infected mouse models and human cohorts, disease severity was associated with a pronounced shift in myeloid balance, characterized by an increased neutrophil‐to‐monocyte ratio. Neutrophils exhibited prolonged retention within the pulmonary microvasculature and formed large co‐aggregates with monocytes. In parallel, severe disease was associated with a defect in classical monocyte activation in the lungs, notably through reduced PD‐L1 upregulation. This defect was not observed in the circulation, indicating tissue‐dependent dysregulation of inflammatory and regulatory markers. Aging further accentuated this imbalance. Both aged mice and elderly patients displayed a reduced proportion of PD‐L1‐expressing lung monocytes, despite enhanced pulmonary neutrophil recruitment. This age‐associated alteration distinguished severe from non‐severe disease and characterized a maladaptive myeloid response to acute viral challenge. Together, these findings identify impaired, compartment‐specific myeloid immune regulation as a central feature of age‐related vulnerability to severe infection. They highlight that tissue‐dependent regulatory failure compounds inflammatory excess as a key determinant of disease outcome and suggest that restoring myeloid regulatory function may offer therapeutic benefit in older individuals during acute respiratory infections.</jats:p>", "alternative-id": [ "10.1111/acel.70588" ], "article-number": "e70588", "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2026-02-13" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "2026-06-05" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 3, "value": "2026-06-12" } ], "author": [ { "affiliation": [ { "name": "Department of Exact Sciences “Ion Ionescu de la Brad” Iasi University of Life Sciences Iași Romania" }, { "name": 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