Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
J Virol. 2010 Mar;84(6):2983-95. doi: 10.1128/JVI.01805-09. Epub 2010 Jan 6.
Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles. BALB/c mice were treated nasally with either cholera toxin (CT), a mutant form of the CT-related Escherichia coli heat-labile enterotoxin designated LT(R192G), or CpG oligodeoxynucleotide. Mice were subsequently challenged with a lethal dose of influenza A/PR/8/34 virus 24 h after the last immunomodulation treatment and either monitored for survival or sacrificed postchallenge for viral and immunological analysis. Treatment with the three immunomodulators prevented or delayed mortality and weight loss, but only CT and LT(R192G) significantly reduced initial lung viral loads as measured by plaque assay. Analysis performed 4 days postinfection indicated that prophylactic treatments with CT, LT(R192G), or CpG resulted in significantly increased numbers of CD4 T cells, B cells, and dendritic cells and altered costimulatory marker expression in the airways of infected mice, coinciding with reduced expression of pulmonary chemokines and the appearance of inducible bronchus-associated lymphoid tissue-like structures in the lungs. Collectively, these results suggest that, despite different immunomodulatory mechanisms, CT, LT(R192G), and CpG induce an initial inflammatory process and enhance the immune response to primary influenza virus challenge while preventing potentially damaging chemokine expression. These studies provide insight into the immunological parameters and immune modulation strategies that have the potential to enhance the nonspecific host response to influenza virus infection.
预防性或治疗性免疫调节是一种非抗原依赖性策略，它诱导非特异性免疫系统激活，从而增强宿主对疾病的防御能力。在这项研究中，我们使用三种已知能促进不同免疫谱的细菌衍生免疫增强剂，研究了预防性免疫调节对流感病毒感染结果的影响。BALB/c 小鼠经鼻腔给予霍乱毒素（CT）、一种命名为 LT(R192G)的 CT 相关大肠杆菌不耐热肠毒素的突变体或 CpG 寡脱氧核苷酸。最后一次免疫调节治疗后 24 小时，小鼠用致死剂量的流感 A/PR/8/34 病毒进行攻击，并监测其存活情况或攻毒后处死进行病毒和免疫学分析。三种免疫调节剂的治疗可预防或延迟死亡和体重减轻，但只有 CT 和 LT(R192G)可显著降低通过噬斑法测定的初始肺部病毒载量。感染后 4 天的分析表明，CT、LT(R192G)或 CpG 的预防性治疗导致感染小鼠气道中的 CD4 T 细胞、B 细胞和树突状细胞数量显著增加，并改变了共刺激标记物的表达，同时肺趋化因子的表达减少，并出现诱导性支气管相关淋巴组织样结构。总的来说，这些结果表明，尽管免疫调节机制不同，但 CT、LT(R192G)和 CpG 诱导初始炎症过程，并增强对原发性流感病毒攻击的免疫反应，同时防止潜在的破坏性趋化因子表达。这些研究为增强宿主对流感病毒感染的非特异性反应的免疫参数和免疫调节策略提供了见解。
