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Related Experiment Video

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Biolistic Transformation of a Fluorescent Tagged Gene into the Opportunistic Fungal Pathogen Cryptococcus neoformans
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Genetic Interaction Analysis Reveals that Cryptococcus neoformans Utilizes Multiple Acetyl-CoA-Generating Pathways

Katy M Alden1, Andrew J Jezewski1, Sarah R Beattie1

  • 1Department of Pediatrics Carver College of Medicine, University of Iowa, Iowa City Iowa, USA.

Mbio
|June 29, 2022
PubMed
Summary

Cryptococcus neoformans uses acetyl-CoA metabolism enzymes, ATP-citrate lyase (ACL1) and acetyl-CoA synthetase (ACS1), for infection. Their interplay, including the newly identified 2-ketobutyryl-CoA synthetase 1 (KBC1), is crucial for fungal adaptation and survival in the host.

Keywords:
Cryptococcus neoformansacetyl CoAcarbon metabolismfungal pathogenesis

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Area of Science:

  • Mycology and Pathogenesis
  • Molecular and Cellular Biology
  • Biochemistry and Metabolism

Background:

  • Cryptococcus neoformans is a significant human fungal pathogen originating from the environment.
  • Acetyl-CoA metabolism enzymes, ATP-citrate lyase (ACL1) and acetyl-CoA synthetase (ACS1), are vital for C. neoformans infection.
  • Understanding the genetic interactions and metabolic adaptations of C. neoformans during host invasion is critical.

Purpose of the Study:

  • To investigate the genetic interactions between ACL1, ACS1, and a newly identified acetoacetyl-CoA synthetase, renamed 2-ketobutyryl-CoA synthetase 1 (KBC1).
  • To elucidate the roles of these acetyl-CoA metabolism enzymes in C. neoformans fitness and pathogenesis.
  • To explore the metabolic adaptations of C. neoformans in response to the host environment and identify potential antifungal targets.

Main Methods:

  • Genetic interaction studies were performed to analyze double mutants of ACL1, ACS1, and KBC1.
  • In vitro and in vivo fitness assays were conducted, including assessments within macrophages and the central nervous system (CNS).
  • Gene expression levels of ACS1 and KBC1 were compared under in vitro and in vivo conditions.

Main Results:

  • ACL1 and ACS1 form a synthetic lethal gene pair, indicating essentiality when combined.
  • Deletion of ACL1, ACS1, or KBC1 individually reduced fungal fitness within macrophages.
  • The acs1Δ kbc1Δ double mutant exhibited significantly reduced fitness in the CNS compared to single mutants and wild-type, with increased expression of ACS1 and KBC1 in vivo.
  • The acs1Δ mutant showed in vivo hypersusceptibility to fluconazole despite minimal in vitro phenotypes.

Conclusions:

  • C. neoformans utilizes multiple carbon metabolism pathways to adapt to the host environment.
  • The interplay between ACS1 and KBC1 is critical for C. neoformans CNS infection, with roles that are less apparent in vitro.
  • These findings offer insights into the in vivo mechanisms of Acs inhibitors and potential therapeutic strategies against cryptococcal infections.