Mucosal Pre-Exposure to Th17-Inducing Adjuvants Exacerbates Pathology after Influenza Infection
Mucosal Pre-Exposure to Th17-Inducing Adjuvants Exacerbates Pathology after Influenza Infection
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DOI：
10.1016/j.ajpath.2013.09.012
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发表时间：
2014-01-01
影响因子：
6
通讯作者：
Khader, Shabaana A.
中科院分区：
文献类型：
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作者：
Gopal, Radha;Rangel-Moreno, Javier;Khader, Shabaana A.
认为粘膜疫苗赋予对抗粘膜感染性疾病的上级保护。此外，疫苗递送的粘膜途径优先诱导产生T辅助17（Th 17）细胞，其产生细胞因子IL-17。Th 17细胞在介导针对几种粘膜感染性疾病的疫苗诱导的免疫中至关重要。然而，IL-17也是一种有效的促炎细胞因子，我们最近发现IL-17介导小鼠流感感染后的免疫病理学和肺损伤。在目前的研究中，我们测试的假设，粘膜预暴露于Th 17诱导佐剂可以促进疾病恶化后，随后感染流感病毒。小鼠粘膜预暴露于Th 17诱导佐剂，如II型热不稳定肠毒素或霍乱毒素，导致发病率增加，并在随后感染流感病毒时加重肺部炎症。此外，发病率的增加伴随着炎性趋化因子表达的增加和中性粒细胞积聚的增加。重要的是，在预先暴露于Th 17诱导佐剂的小鼠中阻断IL-17途径导致在流感感染小鼠中观察到的炎性表型减弱。我们的研究结果表明，在粘膜Th 17诱导佐剂可用于疫苗策略之前，应仔细研究此类佐剂对疾病加重和感染（如流感）引起的肺损伤的短期和长期有害影响。
Mucosal vaccines are thought to confer superior protection against mucosal infectious diseases. In addition, mucosal routes of vaccine delivery preferentially induce the generation of T helper 17 (Th17) cells, which produce the cytokine IL-17. Th17 cells are critical in mediating vaccine-induced immunity against several mucosal infectious diseases. However, IL-17 is also a potent proinflammatory cytokine, and we recently showed that IL-17 mediates immunopathology and lung injury after influenza infection in mice. In the present study, we tested the hypothesis that mucosal pre-exposure to Th17-inducing adjuvants can promote disease exacerbation upon subsequent infection with influenza virus. Mice mucosally pre-exposed to Th17-inducing adjuvants, such as type II heat-labile enterotoxin or cholera toxin, resulted in increased morbidity and exacerbated lung inflammation upon subsequent infection with influenza virus. Furthermore, the increased morbidity was accompanied by increased expression of inflammatory chemokines and increased accumulation of neutrophils. Importantly, blockade of the IL-17 pathway in mice pre-exposed to Th17-inducing adjuvants resulted in attenuation of the inflammatory phenotype seen in influenza-infected mice. Our findings indicate that, before mucosal Th17-inducing adjuvants can be used in vaccine strategies, the short- and tong-term detrimental effects of such adjuvants on disease exacerbation and lung injury in response to infections, such as influenza, should be carefully studied.