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

“同一个健康”概念认识到人类、动物和环境的健康是密切相关的。钩端螺旋体是钩端螺旋体病的致病菌，钩端螺旋体病是一种影响人类和动物的新兴人畜共患疾病。环境中存在的致病性钩端螺旋体可感染广泛的宿主，该疾病可在意外宿主（如人类或牲畜）中表现为急性甚至致命感染，或在其自然宿主（如小鼠和大鼠）中进展为慢性，主要无症状感染。在牛身上，钩端螺旋体病造成了巨大的经济损失，因为奶制品和牛肉行业的减少，以及高流产率。为了改进这一点，有必要了解在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已经允许理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（如人类和牛）中所见的反应存在明显差异。在这一提议中，我们的目标是应用一个比较分析的巨噬细胞从不同的宿主，如牛，猪，小鼠，仓鼠，和人类感染各种人畜共患钩端螺旋体菌株引起的先天免疫反应，负责不同的疾病结果。这个项目的目标将是了解差异和特异性免疫过程和途径。更具体地说，我们的目标是比较一些toll样受体对钩端螺旋体膜成分的识别，使用结构，生化，基因组学，免疫学，高含量筛选共聚焦显微镜和计算模型方法。该项目将有助于更好地了解驱动钩端螺旋体病宿主特异性的先天免疫机制，并相应地定制宿主定向干预策略。

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.