Itaconate deficiency results in prolonged bacterial burdens and enhanced T cell responses during Francisella tularensis infection

Abstract

Abstract Shifts in cellular metabolism and associated metabolites regulate immune cell function. Recently, it has been shown that the metabolite itaconate plays a critical role in modulating inflammatory responses. Using animals that cannot synthesize itaconate due to an absence of aconitate decarboxylase 1 (AOCD KO), we previously established the lack of itaconate increased susceptibility to high dose challenge with the live vaccine strain (LVS) of Francisella tularensis in terms of both bacterial clearance and survival. However, ACOD KO mice that survived sublethal LVS infection had improved survival against a lethal challenge with virulent F. tularensis (Ftt). Since appropriate coordination of both macrophage and T cell function is essential for surviving Ftt, we next determined if the improved survival of ACOD KO mice was due to alterations in macrophage and/or T cell function. LVS immune ACOD KO mice had increased numbers of lung resident and splenic effector CD4+ and CD8+ T cells compared to WT mice following resolution of infection. Utilizing an in vitro macrophage-T cell co-culture system we did not observe any difference in the ability of WT and ACOD KO T cells to control LVS replication in macrophages when T cells were co-cultured with genetically matched macrophages. However, when macrophage sources were mixed, we observed that regardless of the source of LVS immune T cells, WT macrophages controlled bacterial replication significantly better than ACOD derived macrophages. Together, these findings suggest that the lack of itaconate results in increased and prolonged bacterial burdens in vivo, which leads to greater expansion of effector T cells that confer enhanced protection during Ftt challenge.