Host-pathogen interactions in Mycoplasma bovis pneumonia of cattle

牛支原体已成为引起牛细菌性肺炎的主要原因。它对加拿大牛肉和乳制品行业具有重要的经济意义，是一个福利问题，因为动物患有慢性病，而呼吸道疾病是在牛肉生产中预防性使用抗生素的主要原因。然而，由于缺乏对这种新出现的疾病如何发展的了解，控制方法受到限制。此外，牛分枝杆菌肺炎具有根本的意义，因为许多临床正常的小牛肺部都有牛分枝杆菌，感染的结果在很大程度上取决于宿主因素，而且几乎总是存在其他细菌。因此，这种自然疾病是一种多菌肺疾病的模型，在这种疾病中，随着疾病的发展和进展，肺部会被一系列可预测的细菌感染。这些研究调查了这些细菌和宿主细胞之间的相互作用如何决定感染是得到控制和静止，还是诱导组织损伤和炎症。*首先，我们确定牛分枝杆菌刺激肺部损害的具体方式。假设牛分枝杆菌并不直接损伤肺组织，而是激活肺泡巨噬细胞分泌损害肺的产物。为了研究，巨噬细胞将感染牛分枝杆菌，我们将测量脂肪酶和蛋白酶的产生以及它们对损伤肺细胞和降解对肺功能至关重要的表面活性磷脂和蛋白质的影响。*第二，我们确定病变肺的微环境如何影响巨噬细胞对牛分枝杆菌感染的反应。假说是先前的细胞死亡或炎症导致巨噬细胞对牛分枝杆菌感染做出反应，这种反应促进了炎症和组织损伤，而不是容忍和控制感染。在巨噬细胞感染牛分枝杆菌之前，在体外将巨噬细胞暴露于炎症介质、细菌产物或死亡细胞，并测量其对细菌杀灭、炎症和肺损伤的影响。同样的假设将在体内进行研究，重点是并发感染、肺损伤或炎症如何影响牛分枝杆菌感染的结果。这些研究共同解决宿主-病原体相互作用的基本方面，包括先前存在的组织微环境异常(坏死和炎症)如何影响宿主对细菌感染的反应，从而导致疾病的性质。此外，这些研究提供了有关牛支原体肺炎是如何发展的关键信息，以及为什么一些受感染的牛犊会患病，而另一些则保持健康。这一知识有望为加拿大牛肉和乳制品行业带来直接的实际好处，因为它有助于改进这种重要疾病的控制方法。

Mycoplasma bovis has emerged as a major cause of bacterial pneumonia in cattle. It is of economic importance to the Canadian beef and dairy industries, is a welfare issue because of animal suffering from chronic disease, and respiratory disease is a major reason for preventative use of antibiotics in beef production. However, control methods are limited by a lack of understanding of how this emergent disease develops. Furthermore, M. bovis pneumonia is of fundamental interest because many clinically normal calves have M. bovis bacteria in their lungs, the outcome of infection depends substantially on host factors, and other bacteria are nearly always present. Thus, this natural disease is a model of polymicrobial lung disease, in which the lung is infected by a predictable sequence of bacteria as disease develops and progresses. These studies investigate how interactions among these bacteria and host cells determine whether infection is controlled and quiescent or alternatively induces tissue damage and inflammation. ******First, we determine the specific ways by which M. bovis incites damage to the lung. The hypothesis is that M. bovis does not directly injure lung tissue, but instead activates pulmonary alveolar macrophages to secrete products that damage the lung. To investigate, macrophages will be infected with M. bovis, and we will measure production of lipases and proteases as well as their effect on damaging lung cells and degrading the surfactant phospholipids and proteins that are important for lung function. ******Second, we determine how the microenvironment of the diseased lung influences how macrophages respond to M. bovis infection. The hypothesis is that prior cell death or inflammation causes macrophages respond to M. bovis infection in a way that promotes inflammation and tissue damage instead of tolerating and controlling the infection. Macrophages will be exposed in vitro to inflammatory mediators, bacterial products, or dead cells prior to infecting the macrophages with M. bovis, and the effects on bacterial killing, inflammation and lung damage are measured. The same hypothesis will be investigated in vivo, focusing on how concurrent infection, lung damage or inflammation influence the outcome of M. bovis infection.******Together, these studies address fundamental aspects of host-pathogen interaction including how pre-existing abnormalities of the tissue microenvironment (necrosis and inflammation) influence the host response to bacterial infection and thus the nature of the resulting disease. Further, these studies provide key information on how Mycoplasma bovis pneumonia develops, and why some infected calves develop disease while others remain healthy. This knowledge is expected to be of direct practical benefit for the Canadian beef and dairy industries by leading to methods for improved control of this important disease.