Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, CeLS Building no. 03-05, 28 Medical Drive, Singapore 117597, Singapore.
J Virol. 2010 Jul;84(14):7105-13. doi: 10.1128/JVI.02542-09. Epub 2010 May 5.
The threat of a pandemic spread of highly virulent influenza A viruses currently represents a top global public health problem. Mass vaccination remains the most effective way to combat influenza virus. However, current vaccination strategies face the challenge to meet the demands in a pandemic situation. In a mouse model of severe influenza virus-induced pneumonitis, we observed that prior nasal administration of an attenuated strain of Bordetella pertussis (BPZE1) provided effective and sustained protection against lethal challenge with two different influenza A virus subtypes. In contrast to most cross-protective effects reported so far, the protective window offered upon nasal treatment with BPZE1 lasted up to at least 12 weeks, suggesting a unique mechanism(s) involved in the protection. No significant differences in viral loads were observed between BPZE1-treated and control mice, indicating that the cross-protective mechanism(s) does not directly target the viral particles and/or infected cells. This was further confirmed by the absence of cross-reactive antibodies and T cells in serum transfer and in vitro restimulation experiments, respectively. Instead, compared to infected control mice, BPZE1-treated animals displayed markedly reduced lung inflammation and tissue damage, decreased neutrophil infiltration, and strong suppression of the production of major proinflammatory mediators in their bronchoalveolar fluids (BALFs). Our findings thus indicate that protection against influenza virus-induced severe pneumonitis can be achieved through attenuation of exaggerated cytokine-mediated inflammation. Furthermore, nasal treatment with live attenuated B. pertussis offers a potential alternative to conventional approaches in the fight against one of the most frightening current global public health threats.
高致病性流感病毒的大流行传播威胁目前是一个全球首要的公共卫生问题。大规模疫苗接种仍然是对抗流感病毒最有效的方法。然而，当前的疫苗接种策略在应对大流行情况的需求上面临挑战。在严重流感病毒诱导的肺炎的小鼠模型中，我们观察到，先前经鼻腔给予减毒的百日咳博德特氏菌（BPZE1）株可有效和持续地预防两种不同的甲型流感病毒亚型的致死性攻击。与迄今为止报道的大多数交叉保护作用相反，BPZE1 鼻腔治疗提供的保护窗口持续长达至少 12 周，表明涉及到独特的保护机制。在 BPZE1 处理的小鼠和对照小鼠之间未观察到病毒载量的显著差异，表明交叉保护机制不直接针对病毒颗粒和/或感染细胞。这通过血清转移和体外再刺激实验中分别不存在交叉反应性抗体和 T 细胞进一步得到证实。相反，与感染对照小鼠相比，BPZE1 处理的动物显示出明显减轻的肺部炎症和组织损伤，减少的中性粒细胞浸润以及其支气管肺泡液（BALF）中主要促炎介质的产生的强烈抑制。因此，我们的研究结果表明，通过减轻过度的细胞因子介导的炎症，可以实现对流感病毒引起的严重肺炎的保护。此外，经鼻腔给予活的减毒百日咳博德特氏菌为对抗当前最可怕的全球公共卫生威胁之一提供了一种替代传统方法的潜在选择。
