Sharma-Chawla Niharika, Sender Vicky, Kershaw Olivia, Gruber Achim D, Volckmar Julia, Henriques-Normark Birgitta, Stegemann-Koniszewski Sabine, Bruder Dunja
Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Infection Immunology Group, Institute of Medical Microbiology, Infection Prevention and Control, Otto-von-Guericke University, Magdeburg, Germany.
Infect Immun. 2016 Nov 18;84(12):3445-3457. doi: 10.1128/IAI.00422-16. Print 2016 Dec.
Influenza A virus (IAV) and Streptococcus pneumoniae are major causes of respiratory tract infections, particularly during coinfection. The synergism between these two pathogens is characterized by a complex network of dysregulated immune responses, some of which last until recovery following IAV infection. Despite the high serotype diversity of S. pneumoniae and the serotype replacement observed since the introduction of conjugate vaccines, little is known about pneumococcal strain dependency in the enhanced susceptibility to severe secondary S. pneumoniae infection following IAV infection. Thus, we studied how preinfection with IAV alters host susceptibility to different S. pneumoniae strains with various degrees of invasiveness using a highly invasive serotype 4 strain, an invasive serotype 7F strain, and a carrier serotype 19F strain. A murine model of pneumococcal coinfection during the acute phase of IAV infection showed a significantly increased degree of pneumonia and mortality for all tested pneumococcal strains at otherwise sublethal doses. The incidence and kinetics of systemic dissemination, however, remained bacterial strain dependent. Furthermore, we observed strain-specific alterations in the pulmonary levels of alveolar macrophages, neutrophils, and inflammatory mediators ultimately affecting immunopathology. During the recovery phase following IAV infection, bacterial growth in the lungs and systemic dissemination were enhanced in a strain-dependent manner. Altogether, this study shows that acute IAV infection predisposes the host to lethal S. pneumoniae infection irrespective of the pneumococcal serotype, while the long-lasting synergism between IAV and S. pneumoniae is bacterial strain dependent. These results hold implications for developing tailored therapeutic treatment regimens for dual infections during future IAV outbreaks.
甲型流感病毒（IAV）和肺炎链球菌是呼吸道感染的主要病因，尤其是在合并感染期间。这两种病原体之间的协同作用表现为免疫反应失调的复杂网络，其中一些反应会持续到IAV感染后的恢复阶段。尽管肺炎链球菌的血清型多样性很高，且自引入结合疫苗以来观察到血清型替换现象，但对于IAV感染后严重继发性肺炎链球菌感染易感性增强中肺炎球菌菌株的依赖性知之甚少。因此，我们使用高侵袭性血清型4菌株、侵袭性血清型7F菌株和携带型血清型19F菌株，研究了IAV预感染如何改变宿主对不同侵袭程度的肺炎链球菌菌株的易感性。IAV感染急性期肺炎球菌合并感染的小鼠模型显示，在其他情况下为亚致死剂量时，所有测试的肺炎球菌菌株的肺炎程度和死亡率均显著增加。然而，全身播散的发生率和动力学仍取决于细菌菌株。此外，我们观察到肺泡巨噬细胞、中性粒细胞和炎症介质在肺部水平上存在菌株特异性改变，最终影响免疫病理学。在IAV感染后的恢复阶段，肺部细菌生长和全身播散以菌株依赖性方式增强。总之，这项研究表明，急性IAV感染使宿主易患致命的肺炎链球菌感染，而不论肺炎球菌血清型如何，而IAV与肺炎链球菌之间的长期协同作用则取决于细菌菌株。这些结果对未来IAV爆发期间双重感染的定制治疗方案的开发具有启示意义。
