Stimulating innate immunity to protect against Ebola virus infection

抽象的。丝状病毒如埃博拉病毒和马尔堡病毒是A类病原体（提供免疫原性的病原体）。 对国家安全和公共卫生的最高风险）在NIAID的新兴传染病名单上， 它们易于传播，死亡率高，并可能被用作生物恐怖主义武器。有必要 用于快速起效、易于使用和更有效的药物，以预防埃博拉病毒并提高生存率 病毒感染。开发中的疫苗需要至少10天的时间使受试者产生免疫力，因此是有效的。 对治疗新感染的患者或保护未接种疫苗的医疗保健提供者没有用， 紧急情况下的应急反应人员。正在研究的抗生素和抗体鸡尾酒需要 静脉输注和耐药性可通过随机或定向病毒突变而产生。一种替代的和 保护免受埃博拉病毒感染的潜在协同方法是刺激 宿主免疫系统抵抗病毒感染。巨噬细胞和树突状细胞通常是第一批细胞 感染了埃博拉病毒一旦进入，病毒复制并表达干扰宿主的蛋白质 细胞阻止病毒感染的能力。该病毒还引起宿主细胞分泌促炎细胞因子， 趋化因子吸引其他骨髓细胞传播感染并导致免疫功能障碍 无法控制病毒。干扰素γ（IFNG）快速（数小时内）激活巨噬细胞 和树突状细胞，使他们抵抗感染埃博拉病毒和其他病毒，以及感染的几个 A类兼性胞内细菌病原体，如土拉菌属和伯克霍尔德菌属。因此，IFNG 有可能成为对抗几种致命生物恐怖主义威胁的有效疗法。然而，IFNG有一个非常 体内半衰期短，生物利用度差，在临床前研究中需要腹膜内注射才能获得疗效，以及 具有狭窄的有效窗口，所有这些都限制了蛋白质作为埃博拉治疗的效用。我们创造了一个长期的- 具有上级生物利用度和较长半衰期的作用人IFNG类似物（PEG IFNG）， 皮下注射，并且在动物中比IFNG显著更大的功效。我们假设PEG-IFNG将 在预防埃博拉病毒感染的发病率和死亡率方面， 作为暴露前预防的保护剂和暴露后预防的缓和剂。我们将测试这个 通过比较小鼠PEG IFNG同源物和小鼠IFNG给药前和给药后的功效 感染，以降低小鼠中致死性埃博拉病毒感染的发病率和死亡率，如通过存活率测量的， 体重增加和临床疾病评分。这些研究将带来一种有效的治疗方法， 保护在数小时内，可以很容易地管理（皮下注射）的病人，最近 感染埃博拉病毒，以及在紧急疫情爆发时的第一反应者和医疗保健提供者 形势使用PEG IFNG刺激先天免疫将保护免受埃博拉病毒和多种其他疾病的侵害。 细胞内A类病原体，例如在巨噬细胞内复制的兔热病和伯克霍尔德氏菌。

Abstract. Filoviruses such as Ebola and Marburg viruses are Category A pathogens (pathogens that provide the highest risk to national security and public health) on NIAID's list of emerging infectious diseases due to their ease of dissemination, high mortality rates, and potential use as bioterrorism weapons. There is a need for fast acting, easy to use, and more effective medicines to protect against and improve survival from Ebola virus infection. Vaccines in development require at least 10 days for subjects to develop immunity and thus are not useful for treating newly infected patients or protecting non-vaccinated healthcare providers and first responders in an emergency outbreak situation. Antibiotics and antibody cocktails under study require intravenous infusion and resistance may develop through random or directed virus mutation. An alternative and potentially synergistic approach for protecting against Ebola virus infection is to stimulate the innate arm of the host immune system to resist viral infection. Macrophages and dendritic cells typically are the first cells infected by Ebola virus. Upon entry, the virus replicates and expresses proteins that interfere with the host cell's ability to block viral infection. The virus also causes host cells to secrete proinflammatory cytokines and chemokines that attract other myeloid cells to propagate the infection and results in a dysfunctional immune response unable to control the virus. Interferon gamma (IFNG) quickly (within hours) activates macrophages and dendritic cells so that they resist infection by Ebola and other viruses, as well as infection by several Category A facultative intracellular bacterial pathogens such as Tularemia and Burkholderia. Thus, IFNG has the potential to be an effective therapy against several deadly bioterrorism threats. However, IFNG has a very short in vivo half-life, poor bioavailability, required intraperitoneal injection for efficacy in preclinical studies, and has a narrow efficacy window, all of which limit the protein's utility as an Ebola therapy. We created a long- acting human IFNG analog (PEG IFNG) that has superior bioavailability and a longer half-life following subcutaneous injection and significantly greater efficacy than IFNG in animals. We hypothesize PEG-IFNG will be significantly more effective than IFNG at preventing morbidity and mortality from Ebola virus infection both as a protectant for pre-exposure prophylaxis and as a mitigator for post-exposure prophylaxis. We will test this hypothesis by comparing efficacy of a murine PEG IFNG homolog and murine IFNG administered pre and post infection for reducing morbidity and mortality from lethal Ebola virus infection in mice, as measured by survival, weight gain and clinical sickness scores. These studies will lead to an effective treatment that confers protection within hours and which can be administered easily (subcutaneous injection) to patients who recently contracted Ebola virus, as well as to first responders and healthcare providers in an emergency outbreak situation. Stimulating innate immunity using PEG IFNG will protect against Ebola virus and multiple other intracellular Category A pathogens such as Tularemia and Burkholderia that replicate within macrophages.