Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific

• Published in: Frontiers in immunology 2021-11, Vol.12, p.749504-749504
• Main Authors: Kastelberg, Bridget, Ayubi, Tariq, Tubau-Juni, Nuria, Leber, Andrew, Hontecillas, Raquel, Bassaganya-Riera, Josep, Kale, Shiv D
• Format: Article
• Language: English
• Subjects: Animals; Aspergillosis; aspergillus fumigalus; Aspergillus fumigatus; Cell Line; defense; Epithelial Cells - metabolism; Epithelial Cells - microbiology; fungi; Glycolysis; Humans; Hyphae; Immunology; Macrophages - metabolism; Macrophages - microbiology; Male; Mice; Mice, Knockout; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Neutrophils - metabolism; Neutrophils - microbiology; NLRX1; nod-like proteins; Oxidative Stress; Reactive Oxygen Species - metabolism; Spores, Fungal
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.749504

The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus . In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.