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Human Brain Organoids: A New Model to Study Cryptococcus neoformans Neurotropism.

Alfred T Harding1,2, Lee Gehrke1,2, Jatin M Vyas3,4,5,6

  • 1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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Summary

Human cerebral organoids offer a novel model for studying fungal infections in the central nervous system (CNS). This approach provides insights into fungal pathogenesis and potential therapeutic strategies for diseases like cryptococcal meningitis.

Keywords:
Cryptococcus neoformanscerebral organoidfungal pathogenmodel system

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Area of Science:

  • Neuroscience
  • Mycology
  • Infectious Diseases

Background:

  • Rising rates of fungal infections in immunocompromised individuals and those with comorbidities like COVID-19.
  • Limited progress in antifungal drug development necessitates better understanding of fungal pathogenesis.
  • Existing mouse models have significant limitations in translating findings to human fungal diseases.

Purpose of the Study:

  • To introduce and validate the human cerebral organoid model for studying fungal CNS infections.
  • To investigate the pathogenesis and dissemination of fungal pathogens, specifically *Cryptococcus neoformans*, within human brain tissue.
  • To assess the utility of organoids in understanding fungal tropism, cellular effects, and potential therapeutic targets.

Main Methods:

  • Generation of human cerebral organoids from human embryonic stem cells.
  • Infection of organoids with *Cryptococcus neoformans* to model central nervous system (CNS) fungal infection.
  • Assessment of organoid morphology, cellular architecture, cytokine release, and pathogen invasion using microscopy and molecular techniques.

Main Results:

  • Human cerebral organoids accurately recapitulate key brain cell types and structures relevant to CNS infection.
  • *Cryptococcus neoformans* was shown to penetrate and invade the organoid tissue, demonstrating CNS tropism.
  • Fungal infection led to alterations in organoid morphology, cellular architecture, and induced cytokine release.

Conclusions:

  • Human cerebral organoids serve as a valuable and relevant model for studying fungal CNS infections, overcoming limitations of traditional animal models.
  • This model provides direct insight into fungal pathogenesis in human-relevant tissue, facilitating the study of fungal dissemination to the brain.
  • The model holds potential for developing novel therapeutic strategies against disseminated fungal diseases, including cryptococcal meningitis.