Role of Diabetes in MERS Coronavirus Pathogenesis

项目总结： 在这里，我们试图确定糖尿病在中东呼吸综合征冠状病毒中的作用 (MERS-CoV)发病机制。MERS-CoV于2012年在沙特阿拉伯出现，导致超过2200人 病死率约为35%的感染。大多数致命的MERS冠状病毒感染与 有共病，糖尿病是最常见的共病。我们发现MERS冠状病毒 在患有糖尿病的小鼠身上，发病机制会恶化。我们将确定 通过确定肺结构变化的作用，确定这种强化疾病的机制， 和免疫反应。在Aim1中，我们将确定2型肺泡细胞的可达性， 与正常小鼠相比，糖尿病小鼠肺泡内MERS冠状病毒靶细胞增多。 我们的数据表明，在感染的最早点，肺泡对MERS高度敏感- 冠状病毒，但正常小鼠肺泡2型细胞不存在。我们将评估粘液和架构 以确定是否有差异可以解释不同的感染。在目标2中，我们 将确定糖尿病小鼠的免疫反应是否与正常小鼠不同。不同之处在于 免疫反应，特别是先天免疫反应，可以解释易感性的差异。 在糖尿病小鼠和正常小鼠身上。在目标3中，我们将确定有效的治疗方法 正常小鼠缺乏糖尿病小鼠，目标是在未来改变这些治疗方法 对并存患者更有效的治疗方法。这项提案将共同决定为什么糖尿病 老鼠和潜在的人类对MERS冠状病毒高度敏感。

Project summary: Here we seek to identify the role of diabetes in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) pathogenesis. MERS-CoV emerged in 2012 in Saudi Arabia leading to over 2200 infections with a ~35% case fatality rate. The majority of lethal MERS-CoV infections are associated with a comorbidity, with diabetes as the top comorbidity. We have found that MERS-CoV pathogenesis is exacerbated in a mouse with pre-existing diabetes. We will determine the mechanism for this enhanced disease by determining the role of the changes in lung architecture, and immune response. In Aim1 we will determine whether accessibility of the Type 2 alveolar cells, the target cells for MERS-CoV in the alveoli, is increased in diabetic mice compared to normal mice. Our data suggests that at the earliest points of infection, the alveoli are highly susceptible to MERS- CoV but normal mouse Type 2 alveolar cells are not. We will evaluate the mucus and architecture of the lungs to determine if there is a difference that could explain the differential infection. In Aim 2, we will determine if the immune response in diabetic mice is different than normal mice. A difference in the immune response, especially innate immune response, could explain the susceptibility differences in diabetic and normal mice. In Aim 3 we will determine whether therapeutics that are effective in normal mice are deficient in diabetic mice with the goal of altering those therapeutics in the future for more effective therapies for comorbid patients. Together this proposal will determine why diabetic mice and potentially humans are highly susceptible to MERS-CoV.