Toll-Like Receptor 2 Mediates Fatal Immunopathology in Mice During Treatment of Secondary Pneumococcal Pneumonia Following Influenza
Toll-Like Receptor 2 Mediates Fatal Immunopathology in Mice During Treatment of Secondary Pneumococcal Pneumonia Following Influenza
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DOI：
10.1093/infdis/jir522
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发表时间：
2011-11-01
影响因子：
6.4
通讯作者：
McCullers, Jonathan A.
中科院分区：
文献类型：
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作者：
Karlstroem, Asa;Heston, Sarah M.;McCullers, Jonathan A.
宿主炎症反应导致流感后继发性细菌性肺炎治疗期间发生的显著免疫病理学。我们进行了目前的研究，以确定在小鼠模型与β-内酰胺类和大环内酯类抗生素的不同结果的机制。氨苄青霉素对重复感染细菌的裂解导致中性粒细胞大量流入肺部，导致实变性肺炎、坏死性肺损伤和显著死亡率。这是通过介导的Toll样受体（TLR）2和TLR4和肺炎链球菌细胞毒素肺炎链球菌溶血素是独立的。阿奇霉素治疗可防止中性粒细胞积聚，并使小鼠免于随后死亡。这种效果是独立的抗菌活性的大环内酯类抗生素，因为双重治疗氨苄青霉素和阿奇霉素对阿奇霉素耐药菌株也能够治愈继发性肺炎。这些数据表明，消除细菌而不裂解加上炎症免疫调节的策略应在临床上进行。
Host inflammatory responses contribute to the significant immunopathology that occurs during treatment of secondary bacterial pneumonia following influenza. We undertook the present study to determine the mechanisms underlying disparate outcomes in a mouse model with beta-lactam and macrolide antibiotics. Lysis of superinfecting bacteria by ampicillin caused an extensive influx of neutrophils into the lungs resulting in a consolidative pneumonia, necrotic lung damage, and significant mortality. This was mediated through Toll-like receptor (TLR) 2 and was independent of TLR4 and the Streptococcus pneumoniae cytotoxin pneumolysin. Treatment with azithromycin prevented neutrophil accumulation and rescued mice from subsequent mortality. This effect was independent of the antibacterial activity of this macrolide since dual therapy with ampicillin and azithromycin against an azithromycin-resistant strain also was able to cure secondary pneumonia. These data suggest that strategies for eliminating bacteria without lysis coupled with immunomodulation of inflammation should be pursued clinically.