Introduction: Influenza A virus (IAV) predisposes for secondary infections with opportunistic bacteria, e.g. Streptococcus pneumoniae (S.pn.). Importantly, hypersusceptibility towards S.pn. even persists during post-IAV recovery. Alveolar type II epithelial cells (AECII) are primary targets of IAV and important effectors of antipneumococcal defense in vivo. However, the role of altered antibacterial AECII response in post-IAV lungs is unknown.

Objectives: The overall goal was to uncover the potential contribution of viral-infection-imprinted AECII to impaired antipneumococcal immunity in the post-IAV lung.

Methods: We used a mouse model for IAV/S.pn. superinfection that combines IAV and clinical pneumococcal isolates of different invasiveness (serotypes 4>7F>19F) which were administered at day 14 post IAV. AECII were purified by FACS, gene expression was analyszed by microarray and epigenetic analyses were conducted by ATAC-seq.

Results and Conclusion: Preceeding IAV infection favored a bacterial strain-dependent, hyper-inflammatory airway cytokine profile during invasive secondary pneumococcal infection, characterized by increased levels of type I and II interferon production by alveolar macrophages and induction of IFN-response genes in AECII. In this context, ATAC-seq of AECII from healthy vs. post-flu lungs revealed several IRG DNA regions to be more accessible in post-flu AECII. We show that post-flu susceptibility to S. pn. persists in bacterial-strain dependent manner. Increased IFN-responses in post-flu AECII during hyperinflammatory, bacterial secondary infection are likely driven by increased IFN-responsiveness of post-flu AECII and increased typeI/II IFN secretion of leukocytes in post-influenza lungs.