Influenza A virus (IAV) is the causative agent of mostly mild to moderate seasonal respiratory infections and several pandemic outbreaks, the most recent of which was reported in 2009. Previous IAV pandemics were associated with an enormous death toll; for example, the 1918 H1N1 pandemic affected hundreds of millions of people globally and resulted in~ 50 million deaths. 1 Microbiologic analyses of patient samples revealed a strong incidence of bacterial pathogens in fatal complications of viral infection. 2 To date, many pieces of epidemiologic and experimental evidence reveal pronounced susceptibility to detrimental bacterial superinfection in IAV-infected individuals. The physiologic mechanisms underlying the fatal synergism between IAV and opportunistic respiratory bacterial pathogens are so far incompletely understood. Among these mechanisms, the depletion 3 or dysfunction 4 of professional phagocytes, attenuation of antimicrobial production 5 or desensitization to microbial-associated molecular patterns (MAMPs) 6 are just a few examples indicating the deactivation of airway antimicrobial defense during IAV infection.

Interleukin 33 (IL-33) is one of 11 members of the IL-1 family of cytokines. Although intracellular IL-33 can act as a potent regulator of stimulated and constitutive gene expression, extracellular IL-33 has pleiotropic downstream effects on cells expressing the specific (primary) IL-33 receptor ST2 (for example, fibroblasts, mast cells, T helper 2 (TH2) cells, resident macrophages, DCs, and type 2 innate lymphoid cells (ILC2)). 7 Furthermore, IL-33 is released after cellular injury and (after enzymatic processing) can thus act as a conserved endogenous danger molecule, also termed ‘alarmin’. 8 IL-33 signaling is reported to have detrimental effects in chronic, noncommunicable lung ailments, whereas its role during respiratory infection greatly differs for the various pathogens and the correlating immune responses mounted against them. 9 Importantly, the impact of a preceding IAV infection on IL-33 production during secondary bacterial pneumonia and, vice versa, the physiologic effects of IL-33 on the course of the secondary infection have so far not been addressed.