Characterizing the Roles of CLPP and CMPK2 in Innate Immune Responses

Abstract

Mitochondria are pleiotropic organelles integral to many processes including energy generation, cell death, signal transduction, and immunity. Consequently, mitochondrial dysfunction can significantly alter cell and tissue function and is increasingly implicated in aging, obesity, cardiovascular diseases, infections, and inflammatory disorders. Mitochondria contain several features such as mtDNA that act as danger signals and activate several innate immune sensors leading to inflammatory responses and activation of type I interferon responses. The different roles of mitochondria in innate immune responses, specifically the links between mitochondrial dysfunction, type I interferon responses, and antiviral immunity in health and disease, are the main topics of this dissertation.

First, I used a mouse model of mitochondrial dysfunction due to deletion of mitochondrial protease CLPP and reported that CLPP knockout mice have steady state activation of type I interferon (IFN-I) signaling and antiviral gene expression. I showed that depletion of the cyclic GMP-AMP (cGAS)-Stimulator of Interferon Genes (STING) DNA sensing pathway reduces steady state IFN-I signaling and abrogates the broad antiviral phenotype of CLPP null cells. Moreover, I reported that CLPP deficiency leads to mitochondrial DNA (mtDNA) instability and packaging alterations. Secondly, I reported that antiviral protein CMPK2 negatively modulates macrophage immune responses. I generated a CMPK2 knockout mice and showed that CMPK2-deficient CD11b+ myeloid cells are hyper-responsive to innate immune stimulation and likely contribute to heightened plasma cytokine production in LPS-challenged CMPK2 knockout mice. At the cellular level, I showed that CMPK2 is highly induced in macrophages after LPS and type I interferon challenge and is present in cytoplasmic, mitochondrial, and nuclear compartments. Overall, my research provides evidence of the multiple ways that mitochondria shape innate immune responses.