Inflammation and Therapy for Respiratory Virus Infection

正在进行的研究重点是探索对急性呼吸道病毒感染的病理炎症反应，并利用这些信息制定创造性的策略，以避免这种疾病的这些致命后遗症。 我们要讨论的第一份手稿是我们正在对益生菌乳杆菌物种的免疫调节能力进行的评估。我们以前已经证明，用活的乳杆菌物种初始化呼吸道粘膜可以促进小鼠从肺炎病毒的致命性感染中存活下来，这一特性被称为异种免疫。乳酸菌引发的结果是病毒回收率适度降低，病毒诱导的促炎细胞因子的产生显著减少；这些发现背后的确切机制仍有待阐明。由于在相似的条件下，B细胞已被证明能促进对呼吸道病毒病原体的异种免疫，在本研究中，我们探讨了B细胞在乳杆菌介导的预防急性肺炎病毒感染中的作用。我们发现，乳杆菌免疫的小鼠的特征是呼吸道免疫球蛋白水平升高，免疫球蛋白Ig G、Ig A和Ig M水平升高，肺组织中有致密的、富含B细胞(B220(+))的支气管周和血管周围浸润物，生发中心与BALT的描述一致。乳杆菌免疫的UMT小鼠和JH小鼠的肺组织中未检测到B细胞，乳杆菌免疫的UMT小鼠也没有特征性的浸润物或呼吸道免疫球蛋白。然而，在野生型和乳杆菌免疫的UMT小鼠中，我们观察到病毒恢复减弱，病毒诱导的促炎细胞因子CCL2、IFNGamma和CXCL10受到严重抑制。此外，植物乳杆菌诱导的B细胞缺陷的UMT和JH小鼠和它们各自的野生型小鼠一样，完全免受致命的小鼠肺炎病毒的感染。我们得出的结论是，B细胞对于乳杆菌介导的异种免疫来说是必不可少的，对于提高对致命性肺炎病毒感染的反应的存活率也不是至关重要的。(Percopo等人，2014年。J.免疫。192：5265-5272。) 在我们的第二篇论文中，我们探讨了干扰素-γ基因缺失在体内对急性肺炎病毒感染的影响。虽然在呼吸道中检测到一种具有复杂的抗病毒和免疫调节特性的细胞因子IFNGamma，但它在肺炎病毒病原体--小鼠肺炎病毒(PVM；副粘病毒科)的感染中的作用尚未得到充分的研究。虽然IFNGamma基因缺失对体重减轻、存活或病毒动力学没有影响，但与野生型相比，IFNbeta、IFNlambda2/3和干扰素刺激的2‘-5’寡腺苷合成酶的表达显著减少。此外，在IFNGamma-/-小鼠中，PVM感染促进了显著的炎症，包括嗜酸性粒细胞和中性粒细胞渗入呼吸道和肺实质，在病毒滴度达到峰值几天后观察到。潜在的机制包括在PVM感染的IFNGamma-/-小鼠中过度产生趋化因子和嗜酸性粒细胞活性细胞因子(CXCL1、CCL11、CCL3和IL5)；同样，IFNGamma在体外积极地拮抗依赖于IL5的嗜酸性粒细胞的存活。我们的结果可能对带有IFNGamma信号缺陷的个体的肺炎病毒感染具有临床意义。(Glineur等人，2014，《病毒学》出版)。 我们的第三份手稿，详细描述了嗜酸性粒细胞在抗病毒宿主防御中的作用，在我们关于AI000943-11项目的报告中进行了讨论(Percopo等人，血液123：743-752)。

Ongoing research focuses on the exploration of pathologic inflammatory responses to acute respiratory virus infection and the use of this information to develop creative strategies to circumvent these lethal sequelae characteristic of this disease. Our first manuscript to be discussed features our ongoing evaluation of the immunomodulatory capacity of probiotic Lactobacillus species. We have shown previously that priming of respiratory mucosa with live Lactobacillus species promotes robust and prolonged survival from an otherwise lethal infection with pneumonia virus of mice, a property known as heterologous immunity. Lactobacillus priming results in a moderate reduction in virus recovery and a dramatic reduction in virus-induced proinflammatory cytokine production; the precise mechanisms underlying these findings remain to be elucidated. Because B cells have been shown to promote heterologous immunity against respiratory virus pathogens under similar conditions, in this study we explore the role of B cells in Lactobacillus-mediated protection against acute pneumovirus infection. We found that Lactobacillus-primed mice feature elevated levels of airway Igs IgG, IgA, and IgM and lung tissues with dense, B cell (B220(+))-enriched peribronchial and perivascular infiltrates with germinal centers consistent with descriptions of BALT. No B cells were detected in lung tissue of Lactobacillus-primed B cell deficient uMT mice or Jh mice, and Lactobacillus-primed uMT mice had no characteristic infiltrates or airway Igs. Nonetheless, we observed diminished virus recovery and profound suppression of virus-induced proinflammatory cytokines CCL2, IFNgamma, and CXCL10 in both wild-type and Lactobacillus-primed uMT mice. Furthermore, Lactobacillus plantarum-primed, B cell-deficient uMT and Jh mice were fully protected from an otherwise lethal pneumonia virus of mice infection, as were their respective wild-types. We conclude that B cells are dispensable for Lactobacillus-mediated heterologous immunity and were not crucial for promoting survival in response to an otherwise lethal pneumovirus infection. (Percopo et al., 2014. J. Immunol. 192:5265-5272.) In our second manuscript, we explored the impact of interferon gamma (IFNgamma) gene deletion on acute pneumovirus infection in vivo. While IFNgamma, a cytokine with complex antiviral and immunomodulatory properties, was detected in the airways in response to infection with the pneumovirus pathogen, pneumonia virus of mice (PVM; Family Paramyxoviridae), its role in promoting disease had not been fully explored. Although the IFNgamma gene-deletion had no impact on weight loss, survival or virus kinetics, expression of IFNbeta, IFNlambda2/3 and IFN-stimulated 2'-5' oligoadenylate synthetases was significantly diminished compared to wild-type counterparts. Furthermore, PVM infection in IFNgamma-/- mice promoted prominent inflammation, including eosinophil and neutrophil infiltration into the airways and lung parenchyma, observed several days after peak virus titer. Potential mechanisms include over-production of chemoattractant and eosinophil-active cytokines (CXCL1, CCL11, CCL3 and IL5) in PVM-infected IFNgamma -/- mice; likewise, IFNgamma actively antagonized IL5-dependent eosinophil survival ex vivo. Our results may have clinical implications for pneumovirus infection in individuals with IFNgamma signaling defects. (Glineur et al., 2014, Virology in press). Our third manuscript, which details the role of eosinophils in antiviral host defense, was discussed in our report on Project AI000943-11 (Percopo et al., Blood 123: 743-752).