Seasonal influenza virus infections cause mild illness in healthy adults, as timely viral clearance is mediated by the functions of cytotoxic T cells. However, avian H5N1 influenza virus infections can result in prolonged and fatal illness across all age groups, which has been attributed to the overt and uncontrolled activation of host immune responses. Here, we investigate how excessive innate immune responses to H5N1 impair subsequent adaptive T cell responses in the lungs. Using recombinant H1N1 and H5N1 strains sharing 6 internal genes, we demonstrate that H5N1 (2:6) infection in mice causes higher stimulation and increased migration of lung dendritic cells to the draining lymph nodes, resulting in greater numbers of virus-specific T cells in the lungs. Despite robust T cell responses in the lungs, H5N1 (2:6)-infected mice showed inefficient and delayed viral clearance compared with H1N1-infected mice. In addition, we observed higher levels of inhibitory signals, including increased PD-1 and interleukin-10 (IL-10) expression by cytotoxic T cells in H5N1 (2:6)-infected mice, suggesting that delayed viral clearance of H5N1 (2:6) was due to the suppression of T cell functions in vivo Importantly, H5N1 (2:6)-infected mice displayed decreased numbers of tissue-resident memory T cells compared with H1N1-infected mice; however, despite the decreased number of tissue-resident memory T cells, H5N1 (2:6) was protected against a heterologous challenge from H3N2 virus (X31). Taken together, our study provides mechanistic insight for the prolonged viral replication and protracted illness observed in H5N1-infected patients.IMPORTANCE Influenza viruses cause upper respiratory tract infections in humans. In healthy adults, seasonal influenza virus infections result in mild disease. Occasionally, influenza viruses endemic in domestic birds can cause severe and fatal disease even in healthy individuals. In avian influenza virus-infected patients, the host immune system is activated in an uncontrolled manner and is unable to control infection in a timely fashion. In this study, we investigated why the immune system fails to effectively control a modified form of avian influenza virus. Our studies show that T cell functions important for clearing virally infected cells are impaired by higher negative regulatory signals during modified avian influenza virus infection. In addition, memory T cell numbers were decreased in modified avian influenza virus-infected mice. Our studies provide a possible mechanism for the severe and prolonged disease associated with avian influenza virus infections in humans.

中文翻译：

---

H5N1 感染期间细胞毒性 T 细胞功能的抑制和组织驻留记忆 T 细胞水平的降低。


季节性流感病毒感染会导致健康成年人出现轻微疾病，因为及时的病毒清除是由细胞毒性 T 细胞的功能介导的。然而，禽 H5N1 流感病毒感染可导致所有年龄段的长期致命疾病，这归因于宿主免疫反应的明显且不受控制的激活。在这里，我们研究了对 H5N1 的过度先天免疫反应如何损害肺部随后的适应性 T 细胞反应。使用共享 6 个内部基因的重组 H1N1 和 H5N1 毒株，我们证明小鼠体内的 H5N1 (2:6) 感染会引起更高的刺激，并增加肺树突状细胞向引流淋巴结的迁移，从而导致小鼠体内产生更多数量的病毒特异性 T 细胞。肺部。尽管肺部 T 细胞反应强劲，但与 H1N1 感染小鼠相比，H5N1 (2:6) 感染小鼠的病毒清除效率低且延迟。此外，我们在 H5N1 (2:6) 感染的小鼠中观察到更高水平的抑制信号，包括细胞毒性 T 细胞增加的 PD-1 和白细胞介素 10 (IL-10) 表达，这表明 H5N1 的病毒清除延迟 (2 :6) 是由于体内 T 细胞功能受到抑制重要的是，与 H1N1 感染的小鼠相比，H5N1 (2:6) 感染的小鼠表现出组织驻留记忆 T 细胞数量减少；然而，尽管组织驻留记忆 T 细胞数量减少，H5N1 (2:6) 仍能免受 H3N2 病毒 (X31) 的异源攻击。总而言之，我们的研究为 H5N1 感染患者中观察到的长期病毒复制和长期疾病提供了机制见解。 重要性 流感病毒引起人类上呼吸道感染。在健康成年人中，季节性流感病毒感染会导致轻度疾病。 有时，在家禽中流行的流感病毒即使在健康个体中也会引起严重和致命的疾病。在禽流感病毒感染的患者中，宿主免疫系统不受控制地激活，无法及时控制感染。在这项研究中，我们调查了为什么免疫系统无法有效控制改良形式的禽流感病毒。我们的研究表明，在修饰型禽流感病毒感染期间，较高的负调控信号会损害对清除病毒感染细胞至关重要的 T 细胞功能。此外，感染改良禽流感病毒的小鼠的记忆T细胞数量减少。我们的研究为人类与禽流感病毒感染相关的严重和长期疾病提供了可能的机制。