H7N9 highly pathogenic avian influenza virus (HPAIV) infection in a human was first reported in 2017. A/duck/Japan/AQ-HE29-22/2017 (H7N9) (Dk/HE29-22), found in imported duck meat at an airport in Japan, possesses a hemagglutinin with a multibasic cleavage site, indicating high pathogenicity in chickens, as in the case of other H7 HPAIVs. In the present study, we examined the pathogenicity of Dk/HE29-22 and the effectiveness of a cap-dependent endonuclease inhibitor (baloxavir) and neuraminidase inhibitors (oseltamivir and zanamivir) against infection with this strain in a macaque model (n = 3 for each group). All of the macaques infected with Dk/HE29-22 showed severe signs of disease and pneumonia even after the virus had disappeared from lung samples. Virus titers in macaques treated with baloxavir were significantly lower than those in the other treated groups. After infection, levels of interferon alpha and beta (IFN-α and IFN-β) in the blood of macaques in the baloxavir group were the highest among the groups, whereas levels of tumor necrosis factor alpha (TNF-α) and interleukin 13 (IL-13) were slightly increased in the untreated group. In addition, immune checkpoint proteins, including programmed death 1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), were expressed at high levels in the untreated group, especially in one macaque that showed severe signs of disease, indicating that negative feedback responses against vigorous inflammation may contribute to disease progression. In the group treated with baloxavir, the percentages of PD-1-, CTLA-4-, and TIGIT-positive T lymphocytes were lower than those in the untreated group, indicating that reduction in virus titers may prevent expression of immune checkpoint molecules from downregulation of T cell responses.

中文翻译：

---

帽依赖性核酸内切酶抑制剂和神经氨酸酶抑制剂对 H7N9 高致病性禽流感病毒在食蟹猴中引起严重病毒性肺炎的疗效

2017 年首次报道了人类感染 H7N9 高致病性禽流感病毒 (HPAIV)。 A/duck/Japan/AQ-HE29-22/2017 (H7N9) (Dk/HE29-22)，在进口鸭肉中发现在日本的机场，具有具有多碱基切割位点的血凝素，表明对鸡具有高致病性，与其他 H7 HPAIV 一样。在本研究中，我们在猕猴模型中检测了 Dk/HE29-22 的致病性以及帽依赖性核酸内切酶抑制剂（巴洛沙韦）和神经氨酸酶抑制剂（奥司他韦和扎那米韦）对抗该菌株感染的有效性（n= 每组 3 个）。即使病毒从肺部样本中消失后，所有感染了 Dk/HE29-22 的猕猴都表现出严重的疾病和肺炎迹象。用巴洛沙韦治疗的猕猴的病毒滴度显着低于其他治疗组。感染后，巴洛沙韦组猕猴血液中的干扰素α和β（IFN-α和IFN-β）水平在各组中最高，而肿瘤坏死因子α（TNF-α）和白细胞介素13水平在各组中最高。 IL-13) 在未治疗组中略有增加。此外，免疫检查点蛋白，包括程序性死亡 1 (PD-1) 和具有 Ig 和 ITIM 结构域的 T 细胞免疫受体 (TIGIT)，在未治疗组中高水平表达，特别是在一只表现出严重疾病迹象的猕猴中，表明针对剧烈炎症的负反馈反应可能有助于疾病进展。在巴洛沙韦治疗组中，PD-1、CTLA-4和TIGIT阳性T淋巴细胞的百分比低于未治疗组，表明病毒滴度的降低可能会阻止免疫检查点分子的表达下调的 T 细胞反应。