An infection with the influenza virus can take very different courses, ranging from mild cold-like symptoms to severe, potentially life-threatening pneumonia. Of particular concern is the fact that influenza renders the lungs more susceptible to secondary bacterial infections. These so-called secondary infections can substantially worsen disease outcomes and, in extreme cases, lead to sepsis.
An international research team led by Prof. Dr. Susanne Herold, Adjunct Faculty member of the ILH, has now identified a key mechanism underlying this increased vulnerability and, at the same time, revealed a promising target for future therapeutic interventions. The findings were published in the renowned Journal of Clinical Investigation.
The study focuses on tissue-resident alveolar macrophages, specialized immune cells located directly within the alveoli that form a crucial first line of defense against inhaled pathogens. During severe influenza infections, however, these protective cells are frequently lost, with far-reaching consequences for pulmonary immune defense.
The researchers demonstrated that severe influenza infection triggers an increased influx of neutrophils into the lung tissue. These immune cells release the signaling molecule TNFSF14, a member of the tumor necrosis factor superfamily known to induce cell death. Uptake of TNFSF14 by alveolar macrophages leads to their demise, resulting in the loss of an essential protective mechanism and facilitating bacterial invasion, which can drive severe disease progression.
“Our findings highlight how early a viral infection can compromise local immune defense in the lung,” explains Dr. Christina Malainou, a Scientific Coordinator of the DZL disease area PALI. “At the same time, they open up new opportunities to intervene in this process in a targeted manner and preserve pulmonary immune function.” Such therapeutic strategies may be relevant not only for influenza-associated pneumonia but also for other severe viral lung diseases, including COVID-19.
In addition to researchers from the German Center for Lung Research (DZL), scientists from Giessen and Marburg University Hospital (UKGM), Justus Liebig University Giessen, the German Center for Infection Research (DZIF), the Cardiopulmonary Institute (CPI), as well as further universities and research institutions in Germany, Spain (University of León) and Argentina (IBioBA) contributed to the study.
Source: Ein Unglück kommt selten allein: Wie eine Grippevirusinfektion das Immunsystem schwächt — JLU
Original publication: Malainou C, Peteranderl C, Ferrero MR et al. TNF Superfamily Member 14 Drives Post-Influenza Depletion of Alveolar Macrophages Enabling Secondary Pneumococcal Pneumonia. J Clin Invest. 2025 Nov 18:e185390. doi:10.1172/JCI185390.
