High-Throughput Screening Identifies Genes Required for Candida albicans Induction of Macrophage Pyroptosis

Autor: Leah E. Cowen, Amanda O. Veri, Michelle E. Maxson, Scott D. Gray-Owen, Michael E. Powers, Melanie Wellington, Kwamaa Duah, Kristy Koselny, Suzanne M. Noble, Sergio Grinstein, Cynthia X. Guo, Damian J. Krysan, Ryan G. Gaudet, Matthew J. O’Meara, Teresa R. O’Meara, Jessie MacAlpine
Přispěvatelé: Kronstad, James W
Rok vydání: 2018
Předmět:
0301 basic medicine
fungal morphogenesis
host-pathogen interaction
Cell morphology
Inbred C57BL
Mice
C. albicans
Candida albicans
2.1 Biological and endogenous factors
2.2 Factors relating to the physical environment
cell wall remodelling
Aetiology
Candida
biology
fungal pathogenesis
pyroptosis
Pyroptosis
Inflammasome
QR1-502
3. Good health
Cell biology
Fungal
Infectious Diseases
Host-Pathogen Interactions
Female
medicine.symptom
Infection
functional genomics
Research Article
medicine.drug
Host–pathogen interaction
Genes
Fungal
Inflammation
macrophage
Microbiology
Vaccine Related
03 medical and health sciences
Immune system
Phagocytosis
inflammasome
Virology
Biodefense
medicine
Genetics
Animals
Immune Evasion
Innate immune system
Prevention
Inflammatory and immune system
Macrophages
biology.organism_classification
Microreview
High-Throughput Screening Assays
Mice
Inbred C57BL
030104 developmental biology
Emerging Infectious Diseases
Genes
innate immune responses
cell wall
fungi
Zdroj: Microbial Cell
mBio, vol 9, iss 4
mBio
mBio, Vol 9, Iss 4, p e01581-18 (2018)
mBio, Vol 9, Iss 4 (2018)
ISSN: 2150-7511
Popis: The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through which C. albicans orchestrates this host response, we performed the first large-scale analysis of C. albicans interactions with mammalian immune cells. We identified 98 C. albicans genes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response to C. albicans infection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed that apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization can occur prior to phagolysosomal rupture by C. albicans hyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response to C. albicans infection.
IMPORTANCE Candida albicans is a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction of C. albicans by innate immune cells, such as macrophages and neutrophils. Although some C. albicans cells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated the C. albicans genes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact with C. albicans and may lead to effective strategies to modulate inflammation induced by fungal infections.
Databáze: OpenAIRE
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