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The Endoplasmic Reticulum-Mitochondrion Tether ERMES Orchestrates Fungal Immune Evasion, Illuminating Inflammasome Responses to Hyphal Signals

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posted on 2023-03-29, 00:54 authored by TM Tucey, J Verma-Gaur, J Nguyen, VL Hewitt, TL Lo, M Shingu-Vazquez, AAB Robertson, JR Hill, FA Pettolino, Travis BeddoeTravis Beddoe, MA Cooper, T Naderer, A Traven
The pathogenic yeast Candida albicans escapes macrophages by triggering NLRP3 inflammasome-dependent host cell death (pyroptosis). Pyroptosis is inflammatory and must be tightly regulated by host and microbe, but the mechanism is incompletely defined. We characterized the C. albicans endoplasmic reticulum (ER)-mitochondrion tether ERMES and show that the ERMES mmm1 mutant is severely crippled in killing macrophages despite hyphal formation and normal phagocytosis and survival. To understand dynamic inflammasome responses to Candida with high spatiotemporal resolution, we established live-cell imaging for parallel detection of inflammasome activation and pyroptosis at the single-cell level. This showed that the inflammasome response to mmm1 mutant hyphae is delayed by 10 h, after which an exacerbated activation occurs. The NLRP3 inhibitor MCC950 inhibited inflammasome activation and pyroptosis by C. albicans, including exacerbated inflammasome activation by the mmm1 mutant. At the cell biology level, inactivation of ERMES led to a rapid collapse of mitochondrial tubular morphology, slow growth and hyphal elongation at host temperature, and reduced exposed 1,3-β- glucan in hyphal populations. Our data suggest that inflammasome activation by C. albicans requires a signal threshold dependent on hyphal elongation and cell wall remodeling, which could fine-tune the response relative to the level of danger posed by C. albicans. The phenotypes of the ERMES mutant and the lack of conservation in animals suggest that ERMES is a promising antifungal drug target. Our data further indicate that NLRP3 inhibition by MCC950 could modulate C. albicansinduced inflammation.

Funding

This work, including the efforts of Travis Beddoe, Thomas Naderer, and Ana Traven, was funded by Department of Health vertical bar National Health and Medical Research Council (NHMRC) (APP1023973, APP1081072, and APP1101562). This work, including the efforts of Jiyoti Verma-Gaur, was funded by Australian Research Council (ARC) (DE140101164).In addition to the grants listed above, this research was supported by a Pfizer Australian Research Fellowship (to T.B.), the Monash Researcher Accelerator Grant (MRA) to A.T., and an Australian Postgraduate Award (APA) to V.L.H.

History

Publication Date

2016-05-01

Journal

mSphere

Volume

1

Issue

3

Article Number

e00074-16

Pagination

18p. (p. 1-18)

Publisher

American Society for Microbiology

ISSN

2379-5042

Rights Statement

© 2016 Tucey et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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