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

“一个健康”的概念认识到，人类、动物和环境的健康是密切相关的。问号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新出现的人畜共患疾病，在世界范围内影响着人类和动物。环境中存在的致病性钩端螺旋体可感染广泛的宿主，该病可能在意外宿主(如人或牲畜)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)中进展为主要无症状的慢性感染。在牛中，钩端螺旋体病是由于奶牛业和肉牛业的减少以及高流产率造成的高经济损失。为了改善这一点，必须了解在不同宿主中诱导的先天免疫反应，因为这是了解不同宿主中不同疾病后果的关键。在小鼠身上进行的许多免疫学实验已经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，我们最近的研究表明，人类和牛等其他哺乳动物宿主的反应明显不同。在这项建议中，我们旨在对来自不同宿主(如牛、猪、小鼠、仓鼠和人类)的巨噬细胞感染不同的人畜共患钩端螺旋体毒株时所激发的先天免疫反应进行比较分析，这些毒株对疾病的不同结果负责。该项目的目标将是了解不同和特定的免疫过程和途径。更具体地说，我们的目标是利用结构、生化、基因组、免疫学、高含量筛选、共聚焦显微镜和计算模型等方法，比较一些Toll样受体对钩端螺旋体膜组分的识别。这个项目应该有助于更好地理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.