Mali International Center for Excellence in Research

马里国际卓越研究中心

基本信息

批准号：
10692173
负责人：
Heinrich Feldmann
金额：
$ 60.01万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10692173
关键词：
2019-nCoV Animal Model Animals Area Arenavirus Back Bacteria Borrelia British COVID testing Camels Cattle Clinical Clinical Research Contracts Coronavirus Crimean-Congo Hemorrhagic Fever Virus Cytomegalovirus Dengue Diagnostic Diagnostic tests Disease Doctor of Philosophy Ebola Etiology Fever Filovirus Flavivirus Follow-Up Studies Future Genetic Geographic Distribution Geographic Locations Hantavirus Hospitals Human Immunoglobulin G Incidence Infection Laboratories Lassa Fever Lassa virus Leptospira Livestock Lujo virus Macaca fascicularis Mali Manuscripts Marburgvirus Mastomys Medical Methodology Middle East Respiratory Syndrome Coronavirus Molecular Biology Monkeypox virus Order Spirochaetales Orthobunyavirus Paramyxovirus Pathogenicity Population Preclinical Testing Prevalence Public Health Publishing Relapsing Fever Reporting Research Respiratory Disease Rift Valley fever virus Rodent Route Sampling Scientist Serology Seroprevalences Serum Site Students Technology Testing Time Togaviridae Training Travel Universities Vaccine Research Vaccines Vesicular stomatitis Indiana virus Virulent Virus Virus Diseases Virus Shedding Work ZIKA Zoonoses adaptive immune response base chikungunya infection coronavirus disease experience experimental study field study human study infected vector rodent infection rate international center member microorganism pathogen pathogenic virus preclinical efficacy programs response serosurvey tool vector vector vaccine

项目摘要

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.

在2010年，我们发表了第一个描述，描述了从马里（Mali）捕获的Mastomys natalensis分离出的遗传学独特菌株，该菌株以前被认为没有Lassa病毒。在过去的十三年中，我们继续进行现场研究，映射撒哈拉以南马里少量地区环境中LASSA病毒的地理分布。通过更好地了解马里这种病毒的流行区域，LASSA计划已转变为旨在定义自然啮齿动物宿主中LASSA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，这些动物可以持续感染不同的LASSA菌株，而不会显示出明显的临床迹象，但通过不同的路线散开病毒（Safronetz，Rosenke，Rosenke 2022）。我们还调查了乳鼠作为螺旋体硼曲杆菌的宿主的可能性，这是发烧发烧的原因。我们发现这些动物支持长期感染，实际上可能是这种引起疾病细菌的未报告的宿主物种。我们还使用乳鼠菌落开始基于物种特异性巨型病毒的疫苗来测试一种自我隔离的疫苗。因此，该菌落为自然宿主的未来LASSA病毒感染研究提供了独特的工具。最近，我们建立了方法和技术，以研究乳豆菌中的先天和适应性免疫反应。（Nuismer等人，PLOS neng 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，我们已经开始项目来确定马里南部人类LASSA病毒感染的发病率。在三个部位进行了两项人类血清分裂研究。在16-44％的所有地点发现IgG血清阳性。有趣的是，在后续研究中，我们确定了6.3％的年感染率。由于没有关于马里的LASSA热的临床报道，这表明可能经常发生无症状和轻度感染。实验研究使用来自Mali的LASSA分离株，指定的soromba，支持这一假设，因为soromba在动物模型中的毒性较小，并且在cynomolgus猕猴中出现了非典型呼吸道疾病。目前正在进行一项涵盖较大地理区域的两部分人类研究。在这项研究中，我们正在研究整个人口的横截面，以寻找LASSA病毒的患病率，并从医院收集临床样本，以确定LASSA发烧的患病率。这项研究将确认并扩大我们以前的结果，并确定人类感染，以确定马里LASSA病毒感染的公共健康重要性。马里田间计划已扩展到包括其他人畜共患病毒，包括其他体育症病毒（Lassa，Lujo），Bunyaviruess（Hantaviruess，Crimean-Congo Holorrhagic Fever病毒（CCHFV），Rift Valley Fever病毒），Filoviruses（Ebola和Marburg），Flavivirgires（Flavivirgirus），包括其他体育症病毒（LASSA，LUJO）监测。（登革热，Zika）和冠状病毒（MERS-COV，SARS-COV-2）。我们还开始测试人类，牲畜和野生动植物物种的血清/血液，以确定人畜共患病原体对马里动物和公共卫生的普遍性和重要性。截至今天，我们可以证明马里骆驼的MERS-COV感染和马里牛的高CCHFV感染率。对于人类，我们可以为黄病毒（登革热病毒，Zika），Bunyaviruses（Hantavirus）和Togaviruses（Chikungunya）感染以及leptospira spp感染的血清学证据。所有这些都为马里人的人类疾病做出了贡献。最近，我们证明了马里南部的埃博拉病毒的血清阳性。这些结果表明，这些人畜共患病原体中的几种被广泛分布，但在整个马里地区都被低估了。（Calvignac-Spencer等人，Arch Virol 2020; Bane等人，Emerm Infect Dis 2021）我们继续测试Favipiravir对Crimean-Congo出血热病毒（CCHFV）和LASSA病毒在动物模型中的临床前功效。此外，我们还使用诸如囊泡口腔炎病毒载体的矢量疫苗来扩展CCHFV和LASSA病毒的疫苗研究。（Hansen等人，微生物2021; Lingas等，Plos Comput Biol，2021）在2020年2月，我们为新兴的SARS-COV-2开发并建立了诊断测试。当时，马里没有任何共同案件，这种情况发生了巨大变化。我们目前正在使用Monkey Pox病毒建立类似的诊断测试程序。 ICER站点（G点）仍然是马里共同测试的4个国家诊断中心之一。尽管自2020年2月以来，由于限制了限制，我们一直无法旅行，但我们继续支持诊断工作，并通过临床研究来维持我们的现场计划。该计划继续教育和培训年轻的马里科学家。目前，西迪·贝恩（Sidy Bane）在巴马科大学（University of Bamako）获得博士学位的研究生学士学位的第三年。他最近发表了关于马里南部埃博拉病毒流行的手稿。最近雇用了一名新的实验室成员Fatoumata Camara。她将继续进行分子生物学培训，并将担任实验室技术员。她将支持所有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，以在2022年6月从大学获得医学学位。我们目前在该项目中有四名新学生，并希望他们在2023年6月成功捍卫论文。