22-ICRAD Call 2 Comparative host and species-specific immune responses of macrophages infected with zoonotic Leptospira interrogans

“同一健康”概念认识到人类、动物和环境的健康密切相关。问号钩端螺旋体是钩端螺旋体病的病原体，钩端螺旋体病是一种影响人类和动物的新型人畜共患疾病。存在于环境中的致病性钩端螺旋体可以感染广泛的宿主，并且该疾病可以在偶然宿主（例如人或牲畜）中表现为急性甚至致命的感染，或者在其天然宿主（例如小鼠和大鼠）中发展为慢性的、主要是无症状的感染。在牛中，钩端螺旋体病造成了很高的经济损失，这是由于乳品和牛肉行业的减少以及高流产率。为了改善这一点，必须了解不同宿主中引发的先天免疫反应，因为这是了解不同宿主中所见的不同疾病结果的关键。在小鼠中进行的许多免疫学实验使人们能够了解钩端螺旋体病期间免疫反应的某些方面。然而，我们最近的工作表明，在其他哺乳动物宿主（如人和牛）中观察到的反应存在明显差异。在这项提案中，我们的目标是应用先天免疫反应的比较分析引起的巨噬细胞从不同的主机，如牛，猪，小鼠，仓鼠，和人类感染后，与各种人畜共患病钩端螺旋体菌株，负责不同的疾病后果。这个项目的目标将是了解差异和特定的免疫过程和途径。更具体地说，我们的目标是比较一些Toll样受体识别膜组件的钩端螺旋体，使用结构，生物化学，基因组学，免疫学，高内容筛选共聚焦显微镜和计算建模方法。本研究将有助于更好地了解钩端螺旋体病宿主特异性的先天免疫机制，并据此制定针对宿主的干预策略。

The "One Health" concept recognizes that human, animal, and environment health are closely interrelated. Leptospira interrogans are thecausative bacterial agent of leptospirosis, an emerging zoonotic disease affecting humans and animals, worldwide. Pathogenic leptospirespresent in the environment can infect a broad range of hosts and the disease may appear as an acute, even fatal infection in accidentalhosts, such as humans or livestock, or progress into a chronic, mainly asymptomatic infection in its natural hosts, such as mice and rats. Incattle, leptospirosis is responsible for high economic losses due to reduction in both, dairy and beef industry, and to high abortion rates.Toimprove on this, it is imperative to understand the innate immune responses elicited in different hosts, as this is key to understand thediverse disease outcomes seen in the different hosts. Many immunological experiments conducted in mice have allowed the understandingof some aspects of the immune responses during leptospirosis. However, our recent work has shown clear differences in the response seenin other mammalian hosts such as human and cattle. In this proposal we aim to apply a comparative analysis of the innate immuneresponses elicited by macrophages from divergent hosts such as bovines, pigs, mice, hamsters, and humans upon infection with variouszoonotic Leptospira strains that were responsible for distinct outcomes of disease. The goal of this project will be to understand differentialand specific immunological processes and pathways. More specifically, we aim to compare some Toll-like receptors recognition ofmembrane components of leptospires, using structural, biochemical, genomic, immunological, high content screening confocal microscopyand computational modelling approaches. This project should help to better understand the innate immune mechanisms driving hostspecificities of leptospirosis, and accordingly tailor host directed intervention strategies.