Tanaka Akitaka, Nakamura Shigeki, Seki Masafumi, Fukudome Kenji, Iwanaga Naoki, Imamura Yoshifumi, Miyazaki Taiga, Izumikawa Koichi, Kakeya Hiroshi, Yanagihara Katsunori, Kohno Shigeru
Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, Nagasaki, Japan.
Clin Vaccine Immunol. 2013 Jul;20(7):977-85. doi: 10.1128/CVI.00010-13. Epub 2013 May 1.
Coinfection with bacteria is a major cause of mortality during influenza epidemics. Recently, Toll-like receptor (TLR) agonists were shown to have immunomodulatory functions. In the present study, we investigated the effectiveness and mechanisms of the new TLR4 agonistic monoclonal antibody UT12 against secondary pneumococcal pneumonia induced by coinfection with influenza virus in a mouse model. Mice were intranasally inoculated with Streptococcus pneumoniae 2 days after influenza virus inoculation. UT12 was intraperitoneally administered 2 h before each inoculation. Survival rates were significantly increased and body weight loss was significantly decreased by UT12 administration. Additionally, the production of inflammatory mediators was significantly suppressed by the administration of UT12. In a histopathological study, pneumonia in UT12-treated mice was very mild compared to that in control mice. UT12 increased antimicrobial defense through the acceleration of macrophage recruitment into the lower respiratory tract induced by c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NF-κB) pathway-dependent monocyte chemoattractant protein 1 (MCP-1) production. Collectively, these findings indicate that UT12 promoted pulmonary innate immunity and may reduce the severity of severe pneumonia induced by coinfection with influenza virus and S. pneumoniae. This immunomodulatory effect of UT12 improves the prognosis of secondary pneumococcal pneumonia and makes UT12 an attractive candidate for treating severe infectious diseases.
细菌合并感染是流感流行期间死亡的主要原因。最近，Toll样受体（TLR）激动剂被证明具有免疫调节功能。在本研究中，我们在小鼠模型中研究了新型TLR4激动性单克隆抗体UT12对流感病毒合并感染诱导的继发性肺炎球菌肺炎的有效性和作用机制。在接种流感病毒2天后，给小鼠鼻内接种肺炎链球菌。每次接种前2小时腹腔注射UT12。给予UT12后，存活率显著提高，体重减轻显著减少。此外，给予UT12可显著抑制炎症介质的产生。在组织病理学研究中，与对照小鼠相比，UT12治疗的小鼠肺炎非常轻微。UT12通过加速巨噬细胞募集到由c-Jun氨基末端激酶（JNK）和核因子κB（NF-κB）途径依赖性单核细胞趋化蛋白1（MCP-1）产生所诱导的下呼吸道，增强了抗菌防御。总的来说，这些发现表明UT12促进了肺部固有免疫，可能降低流感病毒和肺炎链球菌合并感染诱导的重症肺炎的严重程度。UT12的这种免疫调节作用改善了继发性肺炎球菌肺炎的预后，使UT12成为治疗严重传染病的有吸引力的候选药物。
