Targeting ACOD1 to attenuate innate immune responses to lethal infections

ABSTRACT A leading cause of microbial infections in hospitalized patients is Gram-negative bacteria, which release the cell wall component lipopolysaccharide (LPS) capable of activating innate immune pathways. The aconitate decarboxylase 1 (ACOD1) is an LPS-inducible mitochondrial enzyme that was previously implicated as a negative innate immune regulator through catalyzing the production of anti-inflammatory itaconate. However, we recently demonstrated that the LPS-induced ACOD1 up-regulation also confers a robust pro-inflammation response in monocytes and macrophages in an itaconate-independent manner. Genetic deletion of ACOD1 or its upstream signaling CDK2 in myeloid cells or pharmacological inhibition of CDK2 (with dinaciclib) uniformly attenuated infection-induced cytokine storm and animal lethality in pre-clinical setting. Clinically, the CDK2- ACOD1 axis was similarly up-regulated and positively correlated with the severity of bacterial infections in a cohort of 40 patients. Thus, our findings have suggested a novel role for ACOD1 in promoting dysregulated innate immune responses to lethal infections. Our central hypothesis is that ACOD1 exerts pro-inflammatory action through interacting with other effectors such as GIMAP7. To test this hypothesis, we will exploit a multifaceted strategy to pursue the following integrated aims. Aim 1: Define the adaptor proteins responsible for CDK2-mediated ACOD1 upregulation in monocytes and macrophages. Aim 2: Identify the effectors responsible for ACOD1-mediated pro-inflammatory cytokine production in monocytes and macrophages. Aim 3: Evaluate the efficacy of anticancer drugs in disrupting ACOD1/GIMAP7 interaction and fighting against lethal infections in preclinical settings. The completion of these studies will provide new insights into the intricate mechanism underlying infection-induced innate immune dysfunction and shed light on the development of novel therapeutic strategy for the management of lethal infections.