Itaconate negatively regulates innate immunity during fungal pneumonia

The innate immune response to pathogens often involves metabolic reprogramming, such as disruption of the Krebs cycle, leading to the accumulation of various metabolites that can further influence innate cell responses during infection. Of these, the immunomodulatory metabolite itaconate has been shown to positively or negatively influence lung immune responses, depending on the pathogen. In the current study, we found that mice deficient in aconitate decarboxylase (Acod1-/- mice), the enzyme that produces itaconate from cis-aconitate, cleared the opportunistic mold Aspergillus fumigatus from the lung more effectively than wild-type (WT) control mice. Augmented fungal clearance in Acod1-/- mice correlated with increased type 17 responses, which themselves correlated with higher IL-1β, PGE2, and γδ T cell levels. Intriguingly, we show that alveolar macrophages and neutrophils from naïve Acod1-/- mice kill A. fumigatus more efficiently. Conversely, the addition of exogenous itaconate to alveolar macrophages and neutrophils from naïve WT mice reduced their antifungal capacity. Mechanistically, alveolar macrophages, but not neutrophils, from naïve Acod1-/- mice demonstrated enhanced ROS production when stimulated with A. fumigatus. We further show that mice with macrophage-specific, but not neutrophil-specific, Acod1 deficiency cleared A. fumigatus more effectively. Itaconate deficiency also protected against fungus-induced mortality during corticosteroid-mediated immunosuppression. Finally, itaconate reduced the antifungal activity of human monocyte-derived macrophages. Collectively, these data identify an immune regulatory role for itaconate during A. fumigatus fungal pneumonia and potentially identify a new therapeutic target for enhancing protection against A. fumigatus.IMPORTANCEFungal infections by invasive molds such as Aspergillus fumigatus are leading causes of morbidity and mortality in immunocompromised individuals, such as patients with hematologic malignancies, and recipients of hematopoietic stem cell transplant (HCT), solid organ transplant (SOT), and cellular therapies. A major shift in the increased incidence of these infections is a result of a rapidly expanding global immunocompromised population due to targeted immunotherapies and biologics for the treatment of cancer, combination therapies, cellular therapies, and bispecific and trispecific antibody therapies. The advancement in these immunomodulatory/immunosuppressive therapies is outpacing our understanding of mechanisms that lead to the development of infections such as invasive aspergillosis. Therefore, the continuing evolution of our understanding of protective and immunoregulatory responses would be expected to reveal new mechanisms that govern susceptibility to fungal pneumonia. To this end, in the current report, we show that the TCA cycle intermediate itaconate hinders lung clearance of A. fumigatus via regulating multiple immune mechanisms. Overall, our study uncovers a new mechanism of immune regulation during fungal pneumonia.