Pathogenic mechanism of severe pneumonia caused by superinfection with influenza virus and oral bacteria

在本研究中，我们发现非致死剂量的流感病毒和几种口服链球菌（变形链球菌、血链球菌、唾液链球菌、马链球菌）的重复感染可使60%以上的小鼠死亡。结果表明，除了先前的非致死性流感感染外，没有严重毒力因子的口服链球菌感染也可能是致死性的。然而，究竟哪种毒力因子是诱导致死性流感-口腔链球菌重复感染的关键媒介，仍是一个问题。用流感HA疫苗免疫小鼠对致命的重复感染没有保护作用。我们发现流感HA免疫不能完全保护小鼠肺泡上皮细胞免受流感感染，从而导致少数流感感染细胞与口腔细菌共感染。结果表明，现有的疫苗佐剂需要增强完全清除流感病毒的保护性免疫反应，以保护流感病毒免受超级感染。在这里，我们测试了两亲性聚（γ-谷氨酸）-接枝- l -苯丙氨酸共聚物（γ-PGA-NPs）是否是系统性流感HA疫苗的有效佐剂，该共聚物是由某些纳豆芽孢杆菌菌株产生的细菌荚膜外聚合物衍生的。与HA单独免疫或HA与铝佐剂混合免疫相比，HA疫苗与γ-PGA-NPs混合皮下免疫可诱导HA再刺激后更高的单核细胞增殖和γ-干扰素（IFN-γ）、白细胞介素(IL)-4和IL-6的产生，不仅增强抗HA中和抗体的产生，而且增强流感病毒特异性细胞介导的免疫反应，包括CTL活性。含γ-PGA-NPs的HA疫苗可保护小鼠免受同源流感病毒致死剂量的攻击。结果表明，将γ-PGA-NPs添加到HA疫苗中可促进有效的保护，并确定γ-PGA-NPs是一种新的、有效的、强效的皮下流感病毒疫苗候选佐剂。少

In the present study, we found that superinfection with non-lethal doses of influenza virus and several kinds of oral streptococci(Streptococcus mutans, S. sanguis, S. salivarius, S. equi) let more than 60% of mice to death. The result suggests that infection with oral streptocci which do not have severe virulent factor can be lethal in addition to prior non-lethal influenza infection. However, it still remains which virulence foctor is a key mediator for induction of lethal influenza-oral streptococcal superinfection.Immunization of mice with influenza HA vaccine did not protect from the lethal superinfection. We found that influenza HA immunization did not protect from influenza infection with mouse alveolar epithelial cells completely, thus, a few of influenza infected cells were co-infected with oral bacteria. The result indicate that the available vaccine adjuvant that enhances protective immnue responses to delete influenza virus completely is needed for protection from the super … More infection. Here we tested whether amphiphilic poly(γ-glutamic acid)-graft-L-phenylalanine copolymers(γ-PGA-NPs), which are derived from a bacterial capsular exopolymer produced by certain Bacillus natto strains, were an effective adjuvant for systemic influenza HA vaccination. Subcutaneous immunization with a mixture of HA vaccine and γ-PGA-NPs induced higher mononuclear cell proliferation and the production of γ-interferon(IFN-γ), interleukin(IL)-4, and IL-6 upon HA restimulation, and enhanced not only anti-HA neutralizing antibody production but also the influenza virus-specific cell-mediated immune response, including CTL activity, compared with immunization with HA alone or a mixture of HA and aluminum adjuvant. HA vaccine with γ-PGA-NPs protected mice against challenges with lethal doses of homologous influenza virus. The results indicate that adding γ-PGA-NPs to the HA vaccine promotes effective protection, and identify γ-PGA-NPs as a new, effective, and potent candidate adjuvant for a subcutaneous influenza virus vaccine. Less