Renal CD169++ resident macrophages are crucial for protection against acute systemic candidiasis.

Disseminated candidiasis remains as the most common hospital-acquired bloodstream fungal infection with up to 40% mortality rate despite the advancement of medical and hygienic practices. While it is well established that this infection heavily relies on the innate immune response for host survival, much less is known for the protective role elicited by the tissue-resident macrophage (TRM) subsets in the kidney, the prime organ for Candida persistence. Here, we describe a unique CD169++ TRM subset that controls Candida growth and inflammation during acute systemic candidiasis. Their absence causes severe fungal-mediated renal pathology. CD169++ TRMs, without being actively involved in direct fungal clearance, increase host resistance by promoting IFN-γ release and neutrophil ROS activity.

ArfGAP Domain-Containing Protein 2 (ADAP2) Integrates Upstream and Downstream Modules of RIG-I Signaling and Facilitates Type I Interferon Production.

Transcription of type I interferon genes during RNA virus infection requires signal communication between several pattern recognition receptor (PRR)-adaptor complexes located at distinct subcellular membranous compartments and a central cytoplasmic TBK1-interferon regulatory factor 3 (IRF3) kinase-transcription factor module. However, how the cell integrates signal transduction through spatially distinct modules of antiviral signaling pathways is less defined. RIG-I is a major cytosolic PRR involved in the control of several RNA viruses. Here we identify ArfGAP domain-containing protein 2 (ADAP2) as a key novel scaffolding protein that integrates different modules of the RIG-I pathway, located at distinct subcellular locations, and mediates cellular antiviral type I interferon production. ADAP2 served to bridge the mitochondrial membrane-bound upstream RIG-I adaptor MAVS and the downstream cytosolic complex of NEMO (regulatory subunit of TBK1), TBK1, and IRF3, leading to IRF3 phosphorylation. Furthermore, independently, ADAP2 also functioned as a major orchestrator of the interaction of TBK1 with NEMO and IRF3. Mutational and in vitro cell-free reconstituted RIG-I signaling assay-based analyses identified that the ArfGAP domain of ADAP2 mediates the interferon response. TRAF3 acted as a trigger for ADAP2 to recruit RIG-I pathway component proteins into a single macromolecular complex. This study provides important novel insights into the assembly and integration of different modules of antiviral signaling cascades.