Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

Yee Ming Khaw, Nupur Aggarwal, William E. Barclay, Eunjoo Kang, Makoto Inoue, Mari L. Shinohara

Research output: Contribution to journalArticlepeer-review

Abstract

Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients, who have previously contracted an infection of Cryptococcus neoformans (Cn). C-IRIS can be lethal but how the immune system triggers life-threatening outcomes in patients is still poorly understood. Here, we establish a mouse model for C-IRIS with Cn serotype A strain H99, which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4+ T cells in immunocompromised Rag1-deficient mice infected with a low inoculum of Cn. The mice with C-IRIS exhibit symptoms which mimic clinical presentations of C-IRIS. This C-IRIS model is Th1-dependent and shows host mortality. This model is characterized with minimal lung injury, but infiltration of Th1 cells in the brain. C-IRIS mice also exhibited brain swelling with resemblance to edema and upregulation of aquaporin-4, a critical protein that regulates water flux in the brain in a Th1-dependent fashion. Our C-IRIS model may be used to advance our understanding of the paradoxical inflammatory phenomenon of C-IRIS in the context of neuroinflammation.

Original languageEnglish (US)
Article number529219
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Sep 29 2020

Keywords

  • Cryptococcus neoformans
  • Th1 cells
  • aquaporin-4
  • astrocytes
  • immune reconstitution inflammatory syndrome
  • interferon-γ
  • neuroinflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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