Supplementary Material for: TLR7 Contributes to the Rapid Progression but Not to the Overall Fatal Outcome of Secondary Pneumococcal Disease following Influenza A Virus Infection

Increased risk for bacterial superinfections substantially contributes to the mortality caused by influenza A virus (IAV) epidemics. While the mechanistic basis for this lethal synergism is still insufficiently understood, immune modulation through the viral infection has been shown to be involved. Since the pattern-recognition receptor (PRR) toll-like receptor 7 (TLR7) is a major sensor for the viral genome, we studied how IAV recognition by TLR7 influences the development of secondary pneumococcal infection. In a mouse model of IAV, TLR7-deficient hosts induced a potent antiviral response and showed unchanged survival. In secondary pneumococcal infection during acute influenza, TLR7ko mice showed a fatal outcome similar to wild-type (WT) hosts, despite significantly delayed disease progression. Also, when bacterial superinfection occurred after virus clearance, WT and TLR7-deficient hosts showed similar mortality, even though we found the phagocytic activity of alveolar macrophages isolated from IAV-pre-infected hosts to be enhanced in TLR7ko over WT mice. Thus, we show that a virus-sensing PRR modulates the progression of secondary pneumococcal infection following IAV. However, the fatal overall outcome in WT as well as TLR7ko hosts suggests that processes distinct from TLR7-triggering override the contribution of this single PRR.

细菌性二重感染风险升高，是甲型流感病毒（Influenza A Virus, IAV）流行导致宿主死亡的重要贡献因素。尽管这种致死性协同作用的分子机制仍未完全阐明，但已有研究证实病毒感染介导的免疫调控异常参与了该过程。由于模式识别受体（pattern-recognition receptor, PRR）Toll样受体7（Toll-like receptor 7, TLR7）是识别病毒基因组的关键受体，本研究探讨了TLR7识别IAV对继发性肺炎链球菌感染进程的影响。在IAV感染的小鼠模型中，TLR7基因敲除宿主可产生强效抗病毒免疫应答，且生存率未受显著影响。在急性流感期继发肺炎链球菌感染的模型中，尽管TLR7敲除小鼠的疾病进程显著延缓，但其致死结局与野生型（wild-type, WT）宿主并无差异。此外，当病毒清除后发生细菌性二重感染时，野生型与TLR7敲除宿主的死亡率同样相近；尽管本研究发现，IAV预感染宿主的肺泡巨噬细胞吞噬活性在TLR7敲除小鼠中较野生型小鼠有所增强。综上，本研究证实，病毒感知型模式识别受体可调控IAV感染后继发性肺炎链球菌感染的进程。然而，野生型与TLR7敲除宿主均出现致死性整体结局，这表明不依赖TLR7激活的其他通路可抵消这一单一模式识别受体的调控作用。