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

Front Immunol. 2020 Sep 29:11:529219. doi: 10.3389/fimmu.2020.529219. eCollection 2020.

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.

Keywords: Cryptococcus neoformans; Th1 cells; aquaporin-4; astrocytes; immune reconstitution inflammatory syndrome; interferon-γ; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cryptococcosis / genetics
  • Cryptococcosis / immunology*
  • Cryptococcosis / pathology
  • Cryptococcus neoformans / immunology*
  • Disease Models, Animal
  • Immune Reconstitution Inflammatory Syndrome
  • Mice
  • Mice, Knockout
  • Th1 Cells / immunology*
  • Th1 Cells / pathology