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

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 infec...

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Autores principales: Kastelberg, Bridget, Ayubi, Tariq, Tubau-Juni, Nuria, Leber, Andrew, Hontecillas, Raquel, Bassaganya-Riera, Josep, Kale, Shiv D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591139/
https://www.ncbi.nlm.nih.gov/pubmed/34790195
http://dx.doi.org/10.3389/fimmu.2021.749504
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author Kastelberg, Bridget
Ayubi, Tariq
Tubau-Juni, Nuria
Leber, Andrew
Hontecillas, Raquel
Bassaganya-Riera, Josep
Kale, Shiv D.
author_facet Kastelberg, Bridget
Ayubi, Tariq
Tubau-Juni, Nuria
Leber, Andrew
Hontecillas, Raquel
Bassaganya-Riera, Josep
Kale, Shiv D.
author_sort Kastelberg, Bridget
collection PubMed
description 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 Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via 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 A. fumigatus 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 A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 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 via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.
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spelling pubmed-85911392021-11-16 Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific Kastelberg, Bridget Ayubi, Tariq Tubau-Juni, Nuria Leber, Andrew Hontecillas, Raquel Bassaganya-Riera, Josep Kale, Shiv D. Front Immunol Immunology 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 Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via 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 A. fumigatus 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 A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 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 via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling. Frontiers Media S.A. 2021-11-01 /pmc/articles/PMC8591139/ /pubmed/34790195 http://dx.doi.org/10.3389/fimmu.2021.749504 Text en Copyright © 2021 Kastelberg, Ayubi, Tubau-Juni, Leber, Hontecillas, Bassaganya-Riera and Kale https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Kastelberg, Bridget
Ayubi, Tariq
Tubau-Juni, Nuria
Leber, Andrew
Hontecillas, Raquel
Bassaganya-Riera, Josep
Kale, Shiv D.
Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
title Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
title_full Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
title_fullStr Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
title_full_unstemmed Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
title_short Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific
title_sort nlrx1-regulated defense and metabolic responses to aspergillus fumigatus are morphotype and cell type specific
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591139/
https://www.ncbi.nlm.nih.gov/pubmed/34790195
http://dx.doi.org/10.3389/fimmu.2021.749504
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