Aziz R K, Kansal R, Abdeltawab N F, Rowe S L, Su Y, Carrigan D, Nooh M M, Attia R R, Brannen C, Gardner L A, Lu L, Williams R W, Kotb M
Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Genes Immun. 2007 Jul;8(5):404-15. doi: 10.1038/sj.gene.6364402. Epub 2007 May 24.
Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically well-characterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains=33, n individuals=445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -- but not sex or weight -- was a significant predictor of survival (P=0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (P< or =0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.
对病原体反应的差异受暴露史、环境和宿主遗传状态的影响。我们最近证明，人类白细胞抗原II类等位基因差异是人类侵袭性A组链球菌（GAS）败血症严重程度的主要决定因素。虽然对基因特征明确的人群进行深入的对照分子研究不可行，但现在可以利用基因多样化的重组近交BXD小鼠群体来确定遗传和环境风险因素。我们在本研究中的目标是标准化模型，并确定影响侵袭性感染结果的遗传和非遗传协变量。尽管有共同的祖先，但各种BXD品系（n品系 = 33，n个体 = 445）在存活率上表现出显著差异。所有品系的小鼠都发生了菌血症，但在疾病严重程度、细菌播散和死亡率方面表现出相当大的差异。菌血症和存活率呈现出预期的负相关。在非遗传因素中，年龄——而非性别或体重——是存活率的显著预测因素（P = 0.0005）。为了尽量减少非遗传变异性，我们将进一步的分析限制在40 - 120日龄的小鼠，并计算了校正后的相对存活指数，该指数反映了动物感染后存活的天数，并根据所有显著协变量进行了标准化。遗传背景（品系）是决定易感性的最显著因素（P≤0.0001），从而强调了宿主遗传变异在决定对严重GAS败血症易感性方面的强大作用。该模型提供了强大的无偏向前遗传学方法，用于绘制特定的数量性状位点和调节GAS败血症严重程度的通路网络。
