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Using mice co-engrafted with a genetically matched human immune system and fetal lung xenograft (fLX), we mapped the immunological events defining successful resolution of SARS-CoV-2 infection in human lung tissues. Viral infection is rapidly cleared from fLX following a peak of viral replication, histopathological manifestations of lung disease and loss of AT2 program, as reported in human COVID-19 patients. Infection resolution is associated with the activation of a limited number of hematopoietic subsets, including inflammatory monocytes and CD3-expressing macrophage-like cells, which are highly enriched in viral RNA and dissipate upon infection resolution. Specific human fibroblast and endothelial subsets also elicit robust antiviral and monocyte chemotaxis signatures, respectively. Notably, systemic depletion of human CD4\u2009+\u2009cells, but not CD3\u2009+\u2009cells, significantly abrogates infection resolution in fLX and induces persistent infection, supporting the dominant role of peripheral CD4\u2009+\u2009monocytes over T-cells in the resolution of acute SARS-CoV-2 infection. Collectively, our findings unravel a comprehensive picture of the immunological events defining effective resolution of SARS-CoV-2 infection in human lung tissues, revealing markedly divergent immunological trajectories between resolving and fatal COVID-19 cases.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013469","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T17:56:36Z","timestamp":1757354196000},"page":"e1013469","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune signatures of SARS-CoV-2 infection resolution in human lung tissues"],"prefix":"10.1371","volume":"21","author":[{"given":"Devin","family":"Kenney","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aoife K.","family":"O\u2019Connell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna 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