Viral pneumonia due to influenza A virus (IAV) is often complicated by secondary bacterial infections, which markedly exacerbates disease severity. On a molecular level, one of the hallmarks of severe IAV infection is the depletion of tissue-resident alveolar macrophages (TR-AMs). Previous studies have associated the period of a depleted TR-AM niche with enhanced susceptibility to secondary bacterial infections; however, the mechanisms underlying post-influenza TR-AM death remain largely unclear. In this study by C. Malainou et al., murine models of IAV infection and IAV/Streptococcus pneumoniae co-infection were combined with single-cell transcriptomics, cell-specific PCR profiling of flow-sorted TR-AMs, and functional ex vivo assays, revealing that TR-AM loss during IAV pneumonia is driven by the neutrophil-derived death-inducing ligand Tumor Necrosis Factor Superfamily Member 14 (TNFSF14).

TNFSF14 signaling was shown to induce TR-AM apoptosis, promoting bacterial outgrowth and worsening disease outcome in the co-infection model. Notably, these effects could be mitigated through intrapulmonary transfer of genetically modified TR-AMs or through antibody-based disruption of the signaling pathway. Elevated TNFSF14 levels in the bronchoalveolar lavage fluid of patients with viral acute respiratory distress syndrom (ARDS) demonstrated the translational potential of these findings, with the TNFSF14 signaling axis appearing as a promising therapeutic target in IAV pneumonia. Ongoing work by the Giessen team aims to determine whether this mechanism is influenza-specific or also relevant in other pneumonia models. Preliminary data suggests that this signaling axis not only shapes host defense during the early infection phase but is also involved in post-viral lung repair, underscoring the complexity of cell–cell interactions within the lung microenvironment during IAV infection.

Find the full article here: https://www.jci.org/articles/view/185390

Source: February 2026 (cpi-online.de)