MDA5 Mediates Antifungal Immunity
Whereas the role of TLR-driven IFN production during fungal immunity has been documented, the role of cytosolic sensing pattern-recognition receptors in this response has not been well studied. In this Top Read, Wang et al. (p. 3058) investigated the role of RIG-I–like receptors (RLRs) during Aspergillus fumigatus infections. dsRNA from A. fumigatus induced secretion of IFN-α and CXCL10 from primary murine fibroblasts. Induction of type I IFNs after A. fumigatus dsRNA challenge was partially dependent on MDA5, a well characterized intracellular receptor for dsRNA, and the adaptor protein MAVS, whereas type III IFN expression was entirely dependent on MDA5/MAVS. Cxcl9 and Cxcl10 expression after pulmonary A. fumigatus challenge required both type I and type III IFNs, further indicating that dsRNA can drive antifungal immunity. Consistent with these observations, mice deficient in either MAVS or MDA5 were more susceptible to pulmonary challenge with A. fumigatus than control mice, confirming that MDA5/MAVS-dependent signaling is required for host resistance against fungal infection. Finally, antifungal effector functions of neutrophils were decreased in MDA5 deficient mice. Thus, this paper demonstrates that fungal factors other than cell wall polysaccharides are responsible for driving the IFN response following respiratory A. fumigatus challenge and reveals an essential role for MDA5/MAVS signaling in regulating IFN expression and antifungal neutrophil killing.
New Treatment for a Rare Primary Immunodeficiency
Activated PI3Kδ (PI3Kδ) syndrome (APDS) is a rare primary immunodeficiency resulting from overactive PI3Kδ signaling affecting both B and T cells. In this Top Read, Diaz et al. (p. 2979) show seletalisib, a PI3Kδ inhibitor, may be a potential therapeutic for APDS based on clinical data from a phase 1b study. Patients were treated with 15–25 mg once daily for 12 wk with the option of continuing in an additional 96-wk extension arm. Although there were some mild adverse events attributed to treatment, seletalisib was generally well tolerated. Investigators determined 57.1% of patients (four of seven) responded to seletalisib treatment. APDS is characterized by lymphoproliferation leading to high numbers of transitional B cells and senescent T cells, and low memory B cell numbers. Seletalisib treatment resulted in improved peripheral lymphadenopathy, including reduction in transitional B cells and a corresponding increase in naive B cells. Serum Ig did not change following seletalisib treatment. Although not significant, there was also a small reduction in senescent CD8 T cells. These data provide early evidence that seletalisib may be an effective therapeutic for treatment of APDS.
Relative Hypoxic Stress Induces Anaphylaxis
Systemic anaphylaxis is triggered by extensive activation of mast cells resulting in the subsequent release of anaphylactic mediators into circulation. Previous work demonstrated that rapid changes in oxygen tension may also result in mast cell degranulation. In this Top Read, Matsuda et al. (p. 2959) show that relative hypoxic stress, resulting from a rapid change from hyperoxia to normoxia, is a risk factor for systemic anaphylaxis. Additional experiments using a variety of knockout mice demonstrated that anaphylaxis induced by relative hypoxic stress was completely dependent on mast cells and/or the TRPA1 channel, which is expressed on the surface of mast cells and acts as a key sensor of relative hypoxic stimulation. Consistent with these observations, in vitro experiments using bone marrow–derived cultured mast cells (BMCMCs) indicated that transmembrane TRPA1 expression is upregulated by hyperoxic exposure and is potentiated by relative hypoxic stimulation, which in turn triggers FcεRI-independent activation via opening of TRPA1 channels. To verify the role of TRPA1-mediated mast cell activation in vivo, mast cell–deficient mice were administered BMCMCs from either wild-type (WT) or TRPA1-deficient mice and then subjected to a rapid shift from hyperoxia to normoxia. Compared with those given WT BMCMCs, mice given TRPA1-deficient BMCMCs did not become anaphylactic. Thus, these data demonstrate that TRPA1-triggered mast cell degranulation is a novel pathway that induces anaphylaxis.
Improving Human IL-10 for Clinical Application
Clinical use of human IL-10 (hIL-10) to treat intestinal inflammatory disease has been limited because of side effects associated with systemic administration. In this Top Read, Fay et al. (p. 3191) investigated if restricting hIL-10 to the intestinal lamina propria may improve its efficacy. The authors genetically fused a nontoxic fragment of cholix (Chx386), an exotoxin secreted by nonpandemic strains of Vibrio cholerae, to hIL-10 (AMT-101) to facilitate transport across intestinal epithelial cells via a transcytosis pathway. In vitro and in vivo studies demonstrated that AMT-101 could efficiently cross healthy human intestinal epithelium via a vesicular transcytosis process, localized to the lamina propria, could activate hIL-10 receptors, and could increase cellular pSTAT3 levels in murine macrophage cells. Furthermore, AMT-101 was taken up by intestinal mucosa in a mouse model of colitis and activated pSTAT3 in the lamina propria with limited systemic distribution. AMT-101 administered to healthy mice by oral gavage or NHPs by colonic spray induced circulating levels of IL-1 receptor antagonist (IL-1Ra), which is induced by IL-10 to modulate the inflammatory actions of IL-1β. Finally, oral administration of AMT-101 in two mouse models of induced colitis prevented plasma cytokine changes and pathological conditions associated with acute inflammation. Thus, this study reports a strategy to locally administer IL-10 to the lamina propria without systemic exposure, providing a novel approach to control inflammation associated with intestinal disease.
- Copyright © 2020 by The American Association of Immunologists, Inc.
