Mali International Center for Excellence in Research

2010年，我们发表了对从马里捕获的纳塔尔蚊虫中分离出的一种基因独特的拉萨病毒株的第一次描述，马里以前被认为没有拉萨病毒。在过去13年中，我们继续进行实地研究，绘制拉萨病毒在整个撒哈拉以南马里周边地区的地理分布情况。随着对这种病毒在马里的流行地区有了更好的了解，LASSA计划已经过渡到旨在确定LASSA在自然啮齿动物宿主中的感染动态和传播性的研究。为此，我们在落基山实验室建立了一群纳塔尔沼虾。一些研究表明，动物可以持续感染不同的拉萨病毒株，没有明显的临床症状，但病毒通过不同的途径传播(Safronetz，Rosenke 2022)。我们还调查了马斯提斯家作为罗氏疏螺旋体宿主的可能性，这种螺旋体是复发发热的原因之一。我们发现，这些动物支持长期感染，实际上可能是这种致病细菌的未报告宿主物种。我们还利用Mastomys的群体开始测试一种基于物种特有的巨细胞病毒的自我传播疫苗。因此，该菌落为未来研究拉萨病毒在自然宿主中的感染提供了独特的工具。最近，我们建立了方法和技术来研究纳塔尔沼虾的先天和获得性免疫反应。(Nuismer等人，PLoS Negl trop Dis 2020；Safronetz等人，Virus 2021；Smith等人，Lab Anim 2021；Tang-Huau等人，Virus 2021) 几年前，我们启动了一些项目，以确定马里南部人类感染拉萨病毒的发病率。在三个地点进行了两项人类血清调查研究；在所有地点都发现了从16%到44%的免疫球蛋白血清阳性。有趣的是，在后续研究中，我们发现年感染率为6.3%。由于马里没有拉沙热的临床报告，这表明可能经常发生无症状和轻度感染。使用来自马里的一种名为Soromba的Lassa分离物进行的实验研究支持这一假设，因为Soromba在动物模型中的毒性较低，并在食蟹猴中表现出一种非典型的呼吸道疾病。一项覆盖更大地理区域的两部分人体研究目前正在进行中。在这项研究中，我们正在检查整个人群的横断面，寻找拉萨病毒的流行情况，并从医院收集临床样本，以确定拉沙热的流行情况。这项研究将确认和扩大我们以前的结果，并确定人类感染情况，以确定马里拉萨病毒感染对公共卫生的重要性。 马里实地方案已扩大到包括其他人畜共患病病毒，包括监测其他人畜共患病病毒(拉萨、卢乔)、布尼亚病毒(汉坦病毒、克里米亚-刚果出血热病毒(CCHFV)、裂谷热病毒)、丝状病毒(埃博拉和马尔堡)、黄病毒(登革热、寨卡病毒)和冠状病毒(MERS-CoV、SARS-CoV-2)。我们还开始检测人、牲畜和野生动物物种的血清/血液，以确定人畜共患病病原体对马里动物和公共卫生的流行率和重要性。到目前为止，我们可以证明MERS冠状病毒在马里骆驼中的感染，以及在马里牛中的高CCHFV感染率。对于人类，我们可以建立黄病毒(登革热、寨卡病毒)、布尼亚病毒(汉坦病毒)、托加病毒(基孔肯雅)感染以及钩端螺旋体感染的血清学证据；所有这些都导致马里的人类疾病。最近，我们在马里南部展示了埃博拉血清阳性反应。这些结果表明，其中几种人畜共患病病原体在马里各地广泛分布，但未得到充分报告。(Calvignac-Spencer等人，Arch Virol 2020；Bane等人，Emerg Infect Dis 2021) 我们继续在动物模型中测试法韦拉韦对克里米亚-刚果出血热病毒(CCHFV)和拉萨病毒的临床前疗效。此外，我们正在使用水泡性口炎病毒载体等载体疫苗扩大CCHFV和Lassa病毒的疫苗研究。(Hansen等人，微生物2021；Lingas等人，PLoS Comput Biol，2021) 2020年2月，我们开发并建立了针对新出现的SARS-CoV-2的诊断检测。当时马里没有任何新冠肺炎病例，情况发生了戏剧性的变化。我们目前正在建立一个类似的猴痘病毒诊断测试计划。ICER站点(G点)仍然是马里4个国家COVID检测诊断中心之一。虽然自2020年2月以来，由于COVID的限制，我们一直无法旅行，但我们继续支持诊断工作，并在临床研究期间维持我们的现场计划。 该项目继续教育和培训马里的年轻科学家。目前，Sidy Bane正在巴马科大学攻读博士学位的第三年。他最近发表了一篇关于马里南部埃博拉疫情的手稿。最近聘请了一名新的实验室成员，Fatoumata Camara。她将继续她的分子生物学培训，并将作为一名实验室技术员工作。她将支持所有实地活动和随后的实验室活动，以支持实地工作。这项人体研究为四名马里学生提供了必要的工作和经验，以便在2022年6月从该大学获得医学学位。我们目前有四名新学生参与该项目，预计他们将在2023年6月成功答辩论文。

In 2010, we published the first description of a genetically unique strain of Lassa virus isolated from Mastomys natalensis captured in Mali, an area previously thought to be free of Lassa virus. Over the last thirteen years we have continued to conduct field studies mapping the geographic distribution of Lassa virus in peridomestic settings across sub-Saharan Mali. With a better understanding of the endemic regions for this virus in Mali, the Lassa program has transitioned into studies aimed at defining the infection dynamics and transmissibility of Lassa in the natural rodent hosts. For this we have established a colony of Mastomys natalensis at the Rocky Mountain Laboratories. Several studies have shown that the animals can be persistently infected with different Lassa strains without showing obvious clinical signs but virus shedding through different routes (Safronetz, Rosenke 2022). We have also investigated the possibility of the Mastomys as a host for a spirochete Borrelia Crocidurae, a cause of relapsing fever. We found that these animals support a long-term infection and may in fact be an unreported host species for this disease-causing bacterium. We have also used the Mastomys colony to begin testing a self-disseminating vaccine based off the species-specific Cytomegalovirus. Thus, this colony provides a unique tool for future Lassa virus infection studies in the natural host. More recently, we have established methodology and technology to study innate and adaptive immune responses in Mastomys natalensis. (Nuismer et al., PLoS Negl Trop Dis 2020; Safronetz et al., Viruses 2021; Smith et al., Lab Anim 2021; Tang-Huau et al., Viruses 2021) A few years back, we have started projects to define the incidence rates of Lassa virus infection in humans in southern Mali. Two human serosurvey studies were conducted at three sites; IgG seroprevalence was found at all sites ranging from 16-44%. Interestingly, in the follow-up study we identified an annual infection rate of 6.3%. As there are no clinical reports of Lassa fever in Mali, this indicates that asymptomatic and mild infections may frequently occur. Experimental studies using a Lassa isolate from Mali, designated Soromba, support this hypothesis as Soromba is less virulent in animal models and presents with an atypical respiratory disease in cynomolgus macaques. A two-part human study covering a larger geographic area is currently underway. In this study we are examining a cross-section of the population as a whole looking for Lassa virus prevalence and collecting clinical samples from hospitals to determine the prevalence of Lassa Fever. This study will confirm and expand upon our previous results and identify human infections to determine the public health importance of Lassa virus infections in Mali. The Mali field program has expanded to include other zoonotic viruses including surveillance for additional arenaviruses (Lassa, Lujo), bunyaviruses (hantaviruses, Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus), filoviruses (Ebola and Marburg), flaviviruses (Dengue, Zika), and coronavirus (MERS-CoV, SARS-CoV-2). We have started to also test serum/blood from humans and livestock and wildlife species to determine the prevalence and importance of zoonotic pathogens for animal and public health in Mali. As of today, we could demonstrate MERS-CoV infections in Malian camels and high CCHFV infection rates in Malian cattle. For humans, we could establish serologic evidence for flavivirus (Dengue, Zika), bunyaviruses (hantavirus), and togaviruses (Chikungunya) infections as well as infections with Leptospira spp.; all contributing to human illness in Mali. Most recently, we demonstrated seroprevalence for Ebola in southern Mali. These results implying that several of these zoonotic pathogens are widely distributed yet underreported throughout Mali. (Calvignac-Spencer et al., Arch Virol 2020; Bane et al., Emerg Infect Dis 2021) We have continued to test the preclinical efficacy of favipiravir for Crimean-Congo hemorrhagic fever virus (CCHFV) and Lassa virus in animal models. In addition, we are expanding vaccine research for CCHFV and Lassa virus using vectored vaccines such as vesicular stomatitis virus vectors. (Hansen et al., Microorganisms 2021; Lingas et al., PLoS Comput Biol, 2021) In February 2020, we developed and established diagnostic testing for the emerging SARS-CoV-2. At that time Mali did not have any COVID cases, a situation that changed dramatically. We are currently establishing a similar diagnostic testing program with Monkey pox virus. The ICER site (Point G) continues to be one of 4 national diagnostic centers for COVID testing in Mali. Although we have not been able to travel since February of 2020 due to COVID restrictions, we continue to support the diagnostic effort and are maintaining our field program through the clinical study. This program continues to educate and train young Malian scientists. Currently, Sidy Bane is in his third year of graduate studies for a PhD degree from the University of Bamako. He has recently published a manuscript on Ebola prevalence in Southern Mali. A new lab member was recently hired, Fatoumata Camara. She will continue her molecular biology training and will be working as a lab technician. She will support all the field activities and subsequent lab activities in support of the field work. The human study has provided four Malian students the necessary work and experience to earn their medical degrees from the University in June of 2022. We currently have four new students on the project and expect them to successfully defend their dissertations in June of 2023.