Mali International Center for Excellence in Research

2010年，我们首次描述了从马里捕获的Mastomys natalensis中分离出的遗传独特的拉沙病毒株，该地区以前被认为没有拉沙病毒。在过去的13年里，我们继续进行实地研究，绘制撒哈拉以南马里境内生活环境中拉沙病毒的地理分布图。随着对该病毒在马里的流行区域有了更好的了解，Lassa计划已过渡到旨在确定Lassa在自然啮齿动物宿主中的感染动力学和传播性的研究。为此，我们在落基山实验室建立了一个Mastomys natalensis的殖民地。几项研究表明，动物可持续感染不同的拉沙病毒株，但未显示出明显的临床体征，但病毒通过不同途径脱落（Safronetz，Rosenke 2022）。我们还调查了Mastomys作为一种螺旋体宿主的可能性，该螺旋体是回归热的一种原因。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。我们还使用乳鼠属群体开始测试一种基于物种特异性巨细胞病毒的自传播疫苗。因此，该菌落为将来在自然宿主中进行拉沙病毒感染研究提供了独特的工具。最近，我们已经建立了方法和技术来研究Mastomys natalensis的先天性和适应性免疫反应。（Nuismer等人，PLoS Negl Trop Dis 2020; Safronetz等人，病毒2021; Smith等人，Lab Anim 2021; Tang-Huau等人，病毒2021） 几年前，我们启动了确定马里南部人类感染拉沙病毒发病率的项目。在三个地点进行了两项人类血清调查研究;在所有地点发现IgG血清阳性率范围为16- 44%。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Lassa分离株（命名为Soromba）的实验研究支持这一假设，因为Soromba在动物模型中毒性较低，并在食蟹猴中表现为非典型呼吸道疾病。目前正在进行一项覆盖更大地理区域的两部分人体研究。在这项研究中，我们正在检查整个人群的横截面，寻找拉沙病毒的流行率，并从医院收集临床样本，以确定拉沙热的流行率。这项研究将证实和扩大我们以前的结果，并确定人类感染，以确定拉沙病毒感染在马里的公共卫生重要性。 马里实地项目已扩大到包括其他人畜共患病毒，包括监测其他沙粒病毒（拉沙病毒、卢霍病毒）、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（埃博拉病毒和马尔堡病毒）、黄病毒（登革热病毒、寨卡病毒）和冠状病毒（中东呼吸综合征冠状病毒、SARS冠状病毒-2）。我们还开始检测人、牲畜和野生动物的血清/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程度和重要性。到目前为止，我们可以证明马里骆驼中的MERS-CoV感染和马里牛中的高CCHFV感染率。对于人类，我们可以建立黄病毒（登革热，寨卡），布尼亚病毒（汉坦病毒）和披膜病毒（基孔肯雅病毒）感染以及钩端螺旋体感染的血清学证据;所有这些都导致了马里的人类疾病。最近，我们在马里南部证实了埃博拉病毒的血清阳性率。这些结果表明，这些人畜共患病病原体中有几种在马里各地分布广泛，但报告不足。（Calvignac-Spencer等人，Arch Virol 2020; Bane等人，急诊感染疾病2021） 我们继续在动物模型中测试法匹拉韦对克里米亚-刚果出血热病毒（CCHFV）和拉沙病毒的临床前疗效。此外，我们正在扩大CCHFV和拉沙病毒的疫苗研究，使用载体疫苗，如水泡性口炎病毒载体。（汉森等人，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病例，情况发生了巨大变化。我们目前正在建立一个类似的诊断测试程序与猴痘病毒。ICER站点（G点）仍然是马里4个国家COVID检测诊断中心之一。尽管由于COVID限制，我们自二零二零年二月以来未能外出，但我们继续支持诊断工作，并通过临床研究维持我们的实地计划。 该方案继续教育和培训马里青年科学家。目前，Sidy Bane在巴马科大学攻读博士学位，目前正在读研究生三年级。他最近发表了一篇关于马里南部埃博拉流行情况的手稿。一个新的实验室成员最近被雇用，法图马塔卡马拉。她将继续她的分子生物学培训，并将作为一个实验室技术员工作。她将支持所有的现场活动和随后的实验室活动，以支持现场工作。这项人类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月从大学获得医学学位。我们目前有四个新的学生在项目上，并希望他们在2023年6月成功地捍卫自己的论文。

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.