Lethal synergism of 2009 pandemic H1N1 influenza virus and Streptococcus pneumoniae coinfection is associated with loss of murine lung repair responses.
Lethal synergism of 2009 pandemic H1N1 influenza virus and Streptococcus pneumoniae coinfection is associated with loss of murine lung repair responses.
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DOI：
10.1128/mbio.00172-11
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发表时间：
2011
期刊：
影响因子：
6.4
通讯作者：
Taubenberger JK
中科院分区：
文献类型：
--
作者：
Kash JC;Walters KA;Davis AS;Sandouk A;Schwartzman LM;Jagger BW;Chertow DS;Li Q;Kuestner RE;Ozinsky A;Taubenberger JK
继发性细菌感染增加了流感病毒感染的疾病严重程度，并在大流行期间大大增加了发病率和死亡率。为了研究流感病毒感染后继发细菌感染，分别给小鼠接种亚致死剂量的2009年季节性H1N1病毒（NIH50）或大流行性H1N1病毒（Mex09）， 48 h后再接种肺炎链球菌。通过体重减轻和生存评估、定量逆转录- pcr （qRT-PCR）检测病毒和细菌、组织病理学、表达微阵列和免疫组织化学来表征疾病。单独接种病毒的小鼠存活率均为100%。接种了Mex09和肺炎链球菌的小鼠出现了严重的体重减轻和100%的死亡率，伴有严重的肺泡炎、细支气管上皮脱落和凋亡标志物cleaved caspase 3的广泛表达。相比之下，接种NIH50和肺炎链球菌的小鼠体重减轻，存活率为100%，肺部病理略有增强。Mex09-S。肺炎链球菌合并感染也导致肺部肺炎链球菌复制增加和感染后期菌血症。全球基因表达谱显示，Mex09-S。肺炎菌合并感染并未引起更严重的炎症反应，但上皮细胞增殖和修复反应明显丧失。细胞增殖标志物MCM7的组织病理学检查显示，除Mex09-S外，各组气道上皮细胞均有明显染色。pneumoniae-infected老鼠。该研究表明，在2009年H1N1大流行病毒感染期间继发细菌感染比季节性流感病毒和细菌合并感染导致更严重的疾病和肺部修复反应的丧失。此外，该研究通过显示致命结果与气道基底上皮细胞损失和相关肺修复反应的相关性，为流感病毒和细菌共感染提供了新的见解。继发性细菌性肺炎导致疾病严重程度增加，并在流感大流行期间造成很大比例的死亡。为了了解细菌和病毒感染相互作用的生物学基础，将小鼠分别感染亚致死剂量的2009年季节性H1N1和大流行性H1N1病毒，并在48 h后感染肺炎链球菌。只有感染了2009年H1N1大流行病毒和肺炎链球菌才会导致死亡率为100%的严重疾病。在致死性共感染期间，宿主对感染的反应分析显示，与肺修复相关的反应显著丧失，这在其他任何实验组中都没有观察到。这组小鼠的肺部也显示出增强的细菌复制。这项研究表明，病毒感染期间肺损伤的程度影响继发性细菌感染的严重程度，并可能有助于解释流感大流行期间死亡率的一些差异。
Secondary bacterial infections increase disease severity of influenza virus infections and contribute greatly to increased morbidity and mortality during pandemics. To study secondary bacterial infection following influenza virus infection, mice were inoculated with sublethal doses of 2009 seasonal H1N1 virus (NIH50) or pandemic H1N1 virus (Mex09) followed by inoculation with Streptococcus pneumoniae 48 h later. Disease was characterized by assessment of weight loss and survival, titration of virus and bacteria by quantitative reverse transcription-PCR (qRT-PCR), histopathology, expression microarray, and immunohistochemistry. Mice inoculated with virus alone showed 100% survival for all groups. Mice inoculated with Mex09 plus S. pneumoniae showed severe weight loss and 100% mortality with severe alveolitis, denuded bronchiolar epithelium, and widespread expression of apoptosis marker cleaved caspase 3. In contrast, mice inoculated with NIH50 plus S. pneumoniae showed increased weight loss, 100% survival, and slightly enhanced lung pathology. Mex09-S. pneumoniae coinfection also resulted in increased S. pneumoniae replication in lung and bacteremia late in infection. Global gene expression profiling revealed that Mex09-S. pneumoniae coinfection did not induce significantly more severe inflammatory responses but featured significant loss of epithelial cell reproliferation and repair responses. Histopathological examination for cell proliferation marker MCM7 showed significant staining of airway epithelial cells in all groups except Mex09-S. pneumoniae-infected mice. This study demonstrates that secondary bacterial infection during 2009 H1N1 pandemic virus infection resulted in more severe disease and loss of lung repair responses than did seasonal influenza viral and bacterial coinfection. Moreover, this study provides novel insights into influenza virus and bacterial coinfection by showing correlation of lethal outcome with loss of airway basal epithelial cells and associated lung repair responses. Secondary bacterial pneumonias lead to increased disease severity and have resulted in a significant percentage of deaths during influenza pandemics. To understand the biological basis for the interaction of bacterial and viral infections, mice were infected with sublethal doses of 2009 seasonal H1N1 and pandemic H1N1 viruses followed by infection with Streptococcus pneumoniae 48 h later. Only infection with 2009 pandemic H1N1 virus and S. pneumoniae resulted in severe disease with a 100% fatality rate. Analysis of the host response to infection during lethal coinfection showed a significant loss of responses associated with lung repair that was not observed in any of the other experimental groups. This group of mice also showed enhanced bacterial replication in the lung. This study reveals that the extent of lung damage during viral infection influences the severity of secondary bacterial infections and may help explain some differences in mortality during influenza pandemics.