Exploring the use of conplastic mice as a model of risk stratification of coronavirus susceptibility

本申请着重于我们和其他人发现的线粒体未折叠蛋白的观察 （UPRmt）导致先天免疫系统的激活。更具体地说，我们的团队已经确定了两个轴 UPRmt，一个由线粒体sirtuin SIRT 3（一种长寿基因）调节，另一个由 雌激素受体α（ERα），是两性异形的主要驱动力。此外，我们还报道了线粒体 DNA（mtDNA）深刻地影响细胞激活UPRmt的能力。我们发现线粒体DNA的变异 在人类mtDNA单倍型之间观察到的变异范围内 人口，足以定义UPRmt是否被激活。因此，这个前提 应用是UPRmt可以提供一个机制解释COVID 19的流行病学在三个 程度.首先，为什么它会影响更严重的老年人;我们假设，SIRT 3的下降， 衰老削弱了诱导UPRmt的能力，从而削弱了先天免疫系统。第二，为什么男性 更受影响;我们假设无法激活男性UPRmt的ERα轴有助于 由于先天免疫反应较弱，它们的敏感性增加。第三，为什么有些人 无症状而其他人死亡：我们假设携带UPRmt激活mtDNA的个体可能是那些 无症状的人，而那些携带mtDNA的人不会导致UPRmt的激活， 可能是那些出现严重症状的人本补充中提出的假设得到进一步支持 最近的研究结果来自父母奖，重点是Conplastic小鼠中的UPRmt， 更健康更长寿。这些小鼠共享相同的核基因组，但仅在线粒体上不同。 基因组最近，我们发现共质体雌性激活了UPRmt， 在雌性Conplastic小鼠中的基因谱富含免疫和抗病毒基因，而Conplastic雄性小鼠则富含免疫和抗病毒基因。 没有这些结果有力地支持了我们的假设，并提高了共质体小鼠可能 代表了一种独特的小鼠模型来剖析COVID 19流行病学的几个方面。此外，我们的 RNAseq分析鉴定了临床批准的药物，这些药物模拟了雌性共发育小鼠的遗传特征， 因此提供了调节免疫特性的潜在药理学手段。基于这些观察 我们提出：具体目标1：比较野生型和 雄性和雌性的Conplastic小鼠。具体目标2：测试是否有模拟遗传学的药理学干预 共质体雌性特征保护野生型小鼠免受冠状病毒感染的不利影响。

This application focuses on the observation that we and others have found that the mitochondrial unfolded protein (UPRmt) leads to the activation of the innate immune system. More specifically, our group has identified two axes of the UPRmt, one regulated by the mitochondrial sirtuin SIRT3, a longevity gene, and another regulated by the estrogen receptor alpha (ERα), a major driver of sexual dimorphism. In addition, we reported that mitochondrial DNA (mtDNA) profoundly influences the ability of cells to activate the UPRmt. We found that variations in mtDNA sequence that are within the same range as variations observed between mtDNA haplotypes in the human population, are sufficient to define whether the UPRmt is activated or not. Therefore, the premise of this application is that the UPRmt may provide a mechanistic explanation to the epidemiology of COVID19 at three levels. First, why it affects more severely elderly individuals; we hypothesize that the decline in SIRT3 during aging weaken the ability to induce the UPRmt and consequently, the innate immune system. Second, why males are more affected; we hypothesize that the inability to activate the ERα axis of the UPRmt in males contributes to their increased sensitivity due to a weaker innate immune response. Third, why some individuals are asymptomatic while others die: we hypothesize that individuals carrying UPRmt-activating mtDNA maybe those who are asymptomatic, while those individuals who carry mtDNA that do not lead to the activation of the UPRmt maybe those who develop severe symptoms. The hypotheses proposed in this supplement are further supported by recent findings from the parent award focusing on the UPRmt in conplastic mice, which were found to be healthier and live longer. These mice share the same nuclear genome but only differ in their mitochondrial genomes. Most recently, we found that the conplastic females activate the UPRmt and that the gene expression profiles in female conplastic mice is enriched in immune and anti-viral genes, while conplastic male mice do not. These results strongly support our hypotheses and raise the possibility that the conplastic mice may represent a unique mouse model to dissect several aspects of the epidemiology of COVID19. Additionally, our RNAseq analysis identified clinically approved drugs that mimic the genetic signatures in female conplastic mice, therefore offering potential pharmacological means to modulate immune profiles. Based on these observations we propose: Specific aim 1: Compare the susceptibility to coronavirus infections between wild-type and conplastic mice in both sexes. Specific aim 2: Test if pharmacological intervention that mimics the genetic signature of conplastic females protects wild-type mice from adverse effect of coronavirus infection.