Newton001: Identification of host and pathogen glucose metabolism modulation during Mycobacterium leprae infection of human macrophages and Schwann ce

根据世界卫生组织的数据，2012年全球麻风病新病例数为189,018例。麻风病虽然不是致命的，但每年在世界上造成超过1.2万例不可逆转的运动残疾和畸形。这种疾病是由麻风分枝杆菌引起的，这是一种强制性的细胞内病原体，优先感染皮肤巨噬细胞和雪旺细胞，造成神经损伤和疤痕，导致麻风的毁容和典型的手脚畸形。巴西每年有33303例麻风病病例，是拉丁美洲受影响最严重的国家，占全球病例数的14%，仅次于印度，每年约有134752例新病例。胞内细菌必须从宿主细胞中获取营养，并通过适应自身的代谢途径或操纵宿主的代谢来生长。了解它们如何从宿主那里获取营养以及如何利用这些营养，将有助于更好地了解感染，并可能启发培养用于疫苗或药物研究的细菌的新方法；这与不能在实验室纯培养中生长的麻风病杆菌特别相关。在本项目中，我们将采用一种新开发的13C通量光谱分析技术来研究麻风分枝杆菌在其宿主细胞中的代谢。麻风分枝杆菌细胞将在小鼠脚垫中培养，然后在含有12C和13c标记的葡萄糖和提取用于分析的代谢物混合物的培养基中培养。我们将使用另一种称为质谱法的技术来确定这些代谢物中12C和13C碳的分布，对数据的计算机分析将揭示麻风分枝杆菌所使用的营养物质及其利用方式的线索。这项工作将发表在同行评议的期刊上，并可能导致培育麻风杆菌和开发新药的新方法。

According to World Health Organization, the number of leprosy new cases in 2012 stood at 189,018 around the world. Although not fatal, leprosy is responsible for more than 12 thousands cases of irreversible motor disability and deformity per year in the world. The disease is caused by the Mycobacterium leprae, an obligatory intracellular pathogen that preferentially infects skin macrophages and Schwann cells causing nerve damage and scarring, which results in the disfigurement and the classic hand and foot deformities of leprosy. Brazil has 33,303 cases/year of leprosy, being the most affected country in Latin America, representing 14 percent of the global number of cases and is surpassed only by India, which has approximately 134,752 new cases per year. Intracellular bacteria must obtain nutrients from their host cell and grow by either adapting their own metabolic pathways or manipulating the metabolism of the host. Understanding how they obtain nutrients from their host and how they utilize them will lead to better understanding the infection and may inspire novel ways to grow the bacteria for vaccine or drug studies; which is particularly relevant to the leprosy bacillus which cannot be grown in pure culture in the laboratory.In this project we will use a newly-developed developed technique called 13C flux spectral analysis to investigate the metabolism of M. leprae in its host cell. The M. leprae cells will be grown in mouse footpads, and then incubated in media containing a mixture of 12C and 13C-labelled glucose and metabolites extracted for analysis. We will use another technique called mass spectrometry to determine the distribution of 12C and 13C carbon in these metabolites and computer analysis of the data will reveal clues to both the nutrients used by M. leprae and how it utilises them. The work will be published in a peer-reviewed journal and may lead to novel approaches to growing the leprosy bacillus and developing new drugs.