Efficacy of a Cap-Dependent Endonuclease Inhibitor and Neuraminidase Inhibitors against H7N9 Highly Pathogenic Avian Influenza Virus Causing Severe Viral Pneumonia in Cynomolgus Macaques
Efficacy of a Cap-Dependent Endonuclease Inhibitor and Neuraminidase Inhibitors against H7N9 Highly Pathogenic Avian Influenza Virus Causing Severe Viral Pneumonia in Cynomolgus Macaques
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DOI：
10.1128/aac.01825-20
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发表时间：
2020-11
影响因子：
4.9
通讯作者：
Saori Suzuki;Cong Thanh Nguyen;Ayako Ogata-Nakahara;A. Shibata;H. Osaka;H. Ishigaki;M. Okamatsu;Y. Sakoda;H. Kida;K. Ogasawara;Y. Itoh
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文献类型：
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作者：
Saori Suzuki;Cong Thanh Nguyen;Ayako Ogata-Nakahara;A. Shibata;H. Osaka;H. Ishigaki;M. Okamatsu;Y. Sakoda;H. Kida;K. Ogasawara;Y. Itoh
2017年首次报告人感染H7N9高致病性禽流感病毒(HPAIV)。在日本机场进口鸭肉中发现的A/DAD/JAPAN/AQ-HE29-22/2017(H7N9)(DK/HE29-22)与其他H7 HPAIV一样，含有一种具有多个碱性裂解位点的血凝素，表明对鸡具有高致病性。摘要H7N9高致病性禽流感病毒(HPAIV)人感染于2017年首次报告。在日本机场进口鸭肉中发现的A/DAD/JAPAN/AQ-HE29-22/2017(H7N9)(DK/HE29-22)与其他H7 HPAIV一样，含有一种具有多个碱性裂解位点的血凝素，表明对鸡具有高致病性。在本研究中，我们在猕猴模型(每组3只)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)对该菌株感染的有效性。所有感染DK/HE29-22的猕猴都表现出严重的疾病和肺炎迹象，即使在病毒从肺样本中消失后也是如此。巴洛沙韦处理组猕猴的病毒滴度显著低于其他处理组。感染后，巴拉沙韦组猕猴血液中干扰素-α和干扰素-β的水平最高，而未治疗组的肿瘤坏死因子-α和白介素13水平略有升高。此外，免疫检查点蛋白，包括程序性死亡1(PD-1)和带有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，表明对剧烈炎症的负反馈反应可能有助于疾病的进展。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阻止免疫检查点分子的表达下调T细胞反应。
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. ABSTRACT 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.