军事医学科学院发现人感染H7N9致病新机制

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军事医学科学院微生物流行病研究所周育森团队联合该院实验动物中心曾林团队、基础医学研究所黎燕团队、上海复旦大学姜世勃团队及德国Inflarx Gmbh 公司首席研究人员郭仁锋团队进行科研攻关，发现人感染H7N9禽流感病毒一种新的致病机制。该病毒通过感染，可导致人体一类免疫蛋白分子——补体系统的过度激活，从而引发急性肺损伤。他们根据这一发现，采用新的治疗策略即通过一种针对过敏毒素C5a的抗体药物来调节补体的分子表达水平，证实可以大大降低“炎症因子风暴”，显著减轻肺组织病理损伤，从而能够有效治疗病毒感染引起的严重肺炎。该项成果发表在最新一期的国际传染病研究领域权威学术期刊《临床传染病杂志》上。论文共同第一作者孙世惠和赵光宇博士在该项研究中发挥了重要作用。         补体是存在于血清和组织液中的一类不耐热的具有酶活性的一组蛋白质。早在19世纪末，人类研究人员即证实，血液中含有一种不耐热的成分，可辅助和补充特异性抗体，介导免疫溶菌、溶血作用，故称为补体。补体是由30余种可溶性蛋白、膜结合性蛋白和补体受体组成的多分子系统，故称为补体系统。补体在人体内发挥着重要的免疫及生理功能，当某些因素导致其表达异常时则会引起疾病损伤。         周育森团队的研究表明，补体介导的免疫病理损伤在严重肺炎发病过程中起到了非常重要的“催化剂”作用。因此，采用靶向抑制补体的免疫治疗策略可以有效治疗病毒感染导致的严重肺炎，为缓解患者病情、拯救患者生命开辟了一条新路。（来源：科技日报沈基飞 陈冬）

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Treatment With Anti-C5a Antibody Improves the Outcome of H7N9 Virus Infection in African Green Monkeys

Shihui Sun1,a, Guangyu Zhao1,a, Chenfeng Liu1, Wei Fan2, Xiaojun Zhou2,Lin Zeng2, Yan Guo1, Zhihua Kou1, Hong Yu1, Junfeng Li1, Renxi Wang3,Yan Li3, Conny Schneider4, Maria Habel4, Niels C. Riedemann4,Lanying Du5, Shibo Jiang5,6, Renfeng Guo4, and Yusen Zhou1
1State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology
2Laboratory Animal Center, Academy of Military Medical Science
3Laboratory of Immunology, Beijing Institute of Basic Medical Sciences, China
4InflaRx GmbH, Jena, Germany
5Lindsley F. Kimball Research Institute, New York Blood Center, New York
6Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College, Fudan University, China
Correspondence: Yusen Zhou, PhD, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China (yszhou{at}bmi.ac.cn).
↵a S. S. and G. Z. contributed equally to this work.


Background. Patients infected with influenza A(H7N9) virus present with acute lung injury (ALI) that is due to severe pneumonia and systemic inflammation. It is often fatal because there are few effective treatment options. Complement activation has been implicated in the pathogenesis of virus-induced lung injury; therefore, we investigated the effect of targeted complement inhibition on ALI induced by H7N9 virus infection.

Methods. A novel neutralizing specific antihuman C5a antibody (IFX-1) was used. This antibody blocked the ability of C5a to induce granulocytes to express CD11b while not affecting the ability of C5b to form the membrane attack complex. African green monkeys were inoculated with H7N9 virus and treated intravenously with IFX-1.

Results. The virus infection led to intense ALI and systemic inflammatory response syndrome (SIRS) in association with excessive complement activation. Anti-C5a treatment in H7N9-infected monkeys substantially attenuated ALI: It markedly reduced the lung histopathological injury and decreased the lung infiltration of macrophages and neutrophils. Moreover, the treatment decreased the intensity of SIRS; the body temperature changes were minimal and the plasma levels of inflammatory mediators were markedly reduced. The treatments also significantly decreased the virus titers in the infected lungs.

Conclusions. Antihuman C5a antibody treatment remarkably reduced the ALI and systemic inflammation induced by H7N9 virus infection. Complement inhibition may be a promising adjunctive therapy for severe viral pneumonia.