VIB-UGent, Center for Inflammation Research (IRC), Ghent, Belgium.
Department of Biomedical Molecular Biology (DBMB), Ghent, Belgium.
Cell Death Dis. 2022 Mar 29;13(3):280. doi: 10.1038/s41419-022-04710-2.
RIPK3 partially protects against disease caused by influenza A virus (IAV) infection in the mouse model. Here, we compared the immune protection of active vaccination with a universal influenza A vaccine candidate based on the matrix protein 2 ectodomain (M2e) and of passive immunization with anti-M2e IgG antibodies in wild type and Ripk3 mice. We observed that the protection against IAV after active vaccination with M2e viral antigen is lost in Ripk3 mice. Interestingly, M2e-specific serum IgG levels induced by M2e vaccination were not significantly different between wild type and Ripk3 vaccinated mice demonstrating that the at least the humoral immune response was not affected by the absence of RIPK3 during active vaccination. Moreover, following IAV challenge, lungs of M2e vaccinated Ripk3 mice revealed a decreased number of immune cell infiltrates and an increased accumulation of dead cells, suggesting that phagocytosis could be reduced in Ripk3 mice. However, neither efferocytosis nor antibody-dependent phagocytosis were affected in macrophages isolated from Ripk3 mice. Likewise following IAV infection of Ripk3 mice, active vaccination and infection resulted in decreased presence of CD8+ T-cells in the lung. However, it is unclear whether this reflects a deficiency in vaccination or an inability following infection. Finally, passively transferred anti-M2e monoclonal antibodies at higher dose than littermate wild type mice completely protected Ripk3 mice against an otherwise lethal IAV infection, demonstrating that the increased sensitivity of Ripk3 mice could be overcome by increased antibodies. Therefore we conclude that passive immunization strategies with monoclonal antibody could be useful for individuals with reduced IAV vaccine efficacy or increased IAV sensitivity, such as may be expected in patients treated with future anti-inflammatory therapeutics for chronic inflammatory diseases such as RIPK inhibitors.
RIPK3 在一定程度上可以保护小鼠免受甲型流感病毒 (IAV) 感染引起的疾病。在这里，我们比较了基于基质蛋白 2 胞外域 (M2e) 的通用流感 A 疫苗候选物的主动免疫接种和抗 M2e IgG 抗体的被动免疫接种在野生型和 Ripk3 小鼠中的免疫保护作用。我们观察到，用 M2e 病毒抗原主动免疫接种后，对 IAV 的保护作用在 Ripk3 小鼠中丧失。有趣的是，M2e 疫苗接种诱导的 M2e 特异性血清 IgG 水平在野生型和 Ripk3 接种小鼠之间没有显著差异，这表明至少在主动免疫接种期间缺乏 RIPK3 不会影响体液免疫反应。此外，在 IAV 攻毒后，M2e 疫苗接种的 Ripk3 小鼠的肺部免疫细胞浸润减少，死亡细胞增加，这表明 Ripk3 小鼠的吞噬作用可能降低。然而，Ripk3 小鼠巨噬细胞中的吞噬作用和抗体依赖性吞噬作用不受影响。同样，在 Ripk3 小鼠感染 IAV 后，主动免疫接种和感染导致肺部 CD8+T 细胞数量减少。然而，目前尚不清楚这是由于疫苗接种不足还是感染后无法产生。最后，被动转移的抗 M2e 单克隆抗体剂量高于同窝野生型小鼠，完全保护 Ripk3 小鼠免受致命的 IAV 感染，这表明 Ripk3 小鼠的敏感性增加可以通过增加抗体来克服。因此，我们得出结论，针对单克隆抗体的被动免疫策略可能对 IAV 疫苗效果降低或 IAV 敏感性增加的个体有用，例如可能预期在未来用于治疗慢性炎症性疾病（如 RIPK 抑制剂）的抗炎治疗的患者中。
