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Phenotyping of the pulmonary immune cell landscape after IAV infection revealed a substantial depletion of the tissue-resident alveolar macrophage (TR-AM) population at day 7, which was associated with increased susceptibility to\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    outgrowth. To elucidate the molecular mechanisms underlying TR-AM depletion, and to define putative targets for treatment, we combined single-cell transcriptomics and cell-specific PCR profiling in an unbiased manner, using in vivo models of IAV infection and IAV and\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    coinfection. The TNF superfamily 14 (TNFSF14) ligand\/receptor axis was revealed as the driving force behind post-influenza TR-AM death during the early infection phase, enabling the transition to pneumococcal pneumonia, whereas intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With mainly neutrophilic expression and high abundance in the bronchoalveolar fluid of patients with severe virus-induced acute respiratory distress syndrome, TNFSF14 emerged as a key determinant of virus-driven lung injury. Targeting the TNFSF14-mediated intercellular communication network in the virus-infected lung can, therefore, improve host defense, minimizing the risk of subsequent bacterial pneumonia and ameliorating the disease outcome.\n                  <\/jats:p>","DOI":"10.1172\/jci185390","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T17:01:47Z","timestamp":1763485307000},"source":"Crossref","is-referenced-by-count":5,"title":["TNF superfamily member 14 drives post-influenza depletion of alveolar macrophages, enabling secondary pneumococcal pneumonia"],"prefix":"10.1172","volume":"136","author":[{"given":"Christina","family":"Malainou","sequence":"first","affiliation":[{"name":"Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), member of the German Center for Infection Research (DZIF), Justus Liebig 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