Tribbles1 and Cop1 cooperate to protect the host duringin vivomycobacterial infection

Abstract

AbstractTuberculosis is a major global health problem and is one of the top 10 causes of death worldwide. There is a pressing need for new treatments that circumvent emerging antibiotic resistance.Mycobacterium tuberculosisparasitises macrophages, reprogramming them to establish a niche in which to proliferate, therefore macrophage manipulation is a potential host-directed therapy if druggable molecular targets could be identified. The pseudokinase Tribbles1 (Trib1) regulates multiple innate immune processes and inflammatory profiles making it a potential drug target in infections. Trib1 controls macrophage function, cytokine production and macrophage polarisation. Despite wide-ranging effects on leukocyte biology, data exploring the roles of Tribbles in infectionin vivoare limited. Here, we identify that human Tribbles 1 is expressed in monocytes and is upregulated at the transcript level after stimulation with mycobacterial antigen. To investigate the mechanistic roles of Tribbles in the host response to mycobacteriain vivo, we used a zebrafishMycobacterium marinum(Mm) infection tuberculosis model. Zebrafish Tribbles family members were characterised and shown to have substantial mRNA and protein sequence homology to their human orthologues.trib1overexpression was host-protective against Mm infection, reducing burden by approximately 50%. Conversely,trib1knockdown exhibited increased infection. Mechanistically,trib1overexpression significantly increased the levels of pro-inflammatory factorsil-1β and nitric oxide. The host-protective effect oftrib1was found to be dependent on the E3 ubiquitin kinase Cop1. These findings highlight the importance of Trib1 and Cop1 as immune regulators during infectionin vivoand suggest that enhancing macrophage TRIB1 levels may provide a tractable therapeutic intervention to improve bacterial infection outcomes in tuberculosis.