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.