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.
Highlights
Immune reconstitution inflammatory syndrome (IRIS) is a pathological condition whereby a recovering immune system paradoxically worsens the patient’s condition by responding excessively to a previously acquired infection [1, 2]
We report a mouse model for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) using Cryptococcus neoformans (Cn) serotype A, which is widespread in the environment [25] and the most commonly identified in HIV patients [26,27,28]
To mimic clinical symptoms of C-IRIS, Rag1−/− mice were reconstituted with CD4+ T cells (106 cells/mouse) by adoptive transfer 3 weeks after infection with Cryptococcus neoformans serotype A H99 (CnH99, 100 yeasts/mouse) (Supplementary Figure 1A), unless otherwise noted
Summary
Immune reconstitution inflammatory syndrome (IRIS) is a pathological condition whereby a recovering immune system paradoxically worsens the patient’s condition by responding excessively to a previously acquired infection [1, 2]. In AIDS patients, C-IRIS is reported in some multiple sclerosis (MS) patients These MS patients had Cryptococcus infection prior to discontinuing Natalizumab treatment [12]. Cessation of Natalizumab treatment is considered to allow T cell influx to the CNS These observations suggest that the history of Cryptococcus infection before the influx of CD4+ T cells to the CNS may be a crucial feature of C-IRIS induction. The immune system is reactivated upon normalization of the estrogen levels, triggering C-IRIS development [17]. These reports suggest that clinical conditions typified by a rapid immune recovery are conducive to the development of C-IRIS
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