Virulence and immunity in Rhodococcus equi

马红球菌是引起马驹严重细菌性肺炎的重要原因，它可以在马驹肺部的主要吞噬细胞内存活。令人惊讶的是，这种细菌竟然能在如此恶劣的环境中存活下来，但它在一个独特的基因结构上有一些基因，一个“致病性岛”，使它能够这样做。我们对这种细菌感染的兴趣不仅在于它给世界各地的养马场造成经济损失和士气低落，而且还在于它与结核分枝杆菌有关，结核分枝杆菌是人类结核病的病原体，感染了超过三分之一的人口。这使得这种生物具有很大的比较医学意义，因为我们可以用它来模拟人类结核病的各个方面，例如测试新的抗菌治疗方法。我们所做的工作是为了在分子水平上非常详细地了解这种细菌是如何能够干扰吞噬细胞的正常杀伤的，特别是什么信号告诉细菌它在吞噬细胞内，以及它如何在这种通常充满敌意的环境中打开它需要生存的蛋白质，关闭它不再需要的蛋白质。我们特别感兴趣的是铁和镁在控制这些开关中的作用，以及“致病性岛”如何与基因组相互作用或“对话”，反之亦然。我们将使用许多先进的技术来研究这一点，包括不同基因的失活。我们将测试许多灭活的基因，看看它们是否降低了这种细菌致病的能力，并将发现我们是否可以使用一种或多种突变体给小马驹口服免疫，这样我们就可以安全地阻止这种可怕的疾病。

Rhodococcus equi is an important cause of a serious bacterial pneumonia in foals that can live inside the main phagocytic cell in their lungs.  It is really surprising that such a hostile environment allows this bacterium to survive, but it has some genes on a unique genetic structure, a "pathogenicity island", that allow it to do so. Our interest in this bacterial infection is not only that it causes economic loss and demoralization on horse-breeding farms around the world but also that it is related to Mycobacterium tuberculosis, the agent of human tuberculosis that infects over one-third of the human population.  This makes this organism of great comparative medical interest, since we may be able to use it to model aspects of tuberculosis in humans, for example testing novel antibacterial treatments. The work we are doing is designed to understand at a very detailed molecular level exactly how this bacterium is able to interfere with normal killing by phagocytic cells, especially what signals tells the bacterium that it is inside a phagocyte and how it then switches on proteins that it needs to survive in this usually hostile environment and switches off the proteins that it no longer needs. We are particularly interested in the role of iron and magnesium in controlling these switches, as well as in how the "pathogenicity island" interacts or "talks" to the genome, and vice versa. We will use many advanced techniques to study this, including inactivation of different genes. We will test many inactivated genes to see if they reduce the ability of this bacterium now to cause disease, and will find out whether we can use one or more of these mutants to immunize young foals by mouth, so that we can safely stop this awful disease.