Capillary leakage provides nutrients and antioxidants for rapid pneumococcal proliferation in influenza-infected lower airways

Sender, Vicky; Hentrich, Karina; Pathak, Anuj; Tan Qian Ler, Alicia; Embaie, Bethel Tesfai; Lundström, Susanna L.; Gaetani, Massimiliano; Bergstrand, Jan; Nakamoto, Rei; Sham, Lok-To; Widengren, Jerker; Normark, Staffan; Henriques-Normark, Birgitta

Influenza A virus (IAV)-related mortality is often due to secondary bacterial infections, primarily by pneumococci. Here, we study how IAV-modulated changes in the lungs affect bacterial replication in the lower respiratory tract (LRT). Bronchoalveolar lavages (BALs) from coinfected mice showed rapid bacterial proliferation 4 to 6 h after pneumococcal challenge. Metabolomic and quantitative proteomic analyses demonstrated capillary leakage with efflux of nutrients and antioxidants into the alveolar space. Pneumococcal adaptation to IAV-induced inflammation and redox imbalance increased the expression of the pneumococcal chaperone/protease HtrA. Presence of HtrA resulted in bacterial growth advantage in the IAV-infected LRT and protection from complement-mediated opsonophagocytosis due to capsular production. Absence of HtrA led to growth arrest in vitro that was partially restored by antioxidants. Pneumococcal ability to grow in the IAV-infected LRT depends on the nutrient-rich milieu with increased levels of antioxidants such as ascorbic acid and its ability to adapt to and cope with oxidative damage and immune clearance.