# Brain neuron damage-mediated respiratory failure and mortality during Cryptococcus-associated immune reconstitution inflammatory syndrome in mice

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $380,976

## Abstract

PROJECT SUMMARY/ABSTRACT
Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is induced in
immunocompromised patients who were pre-infected with Cryptococcus before recovering immune function.
C-IRIS is known to occur in HIV patients who received antiretroviral therapy, which restores immune
components such as CD4+ T cells. C-IRIS is also reported in immunocompromised patients who received a
solid-organ transplant, multiple sclerosis patients who discontinue Natalizumab treatment, and postpartum
women. This suggests that any clinical condition associated with a rapid change in immune status is
conducive to C-IRIS. Patients with C-IRIS typically present with pulmonary dysfunction, brain edema, and
brain lesions. C-IRIS can be fatal. Currently, the mechanism by which immune system reconstitution induces
detrimental signaling in patients with an underlying Cryptococcus infection is poorly understood. To resolve
this significant clinical challenge, we established the first reliable mouse model using the Cryptococcus
neoformans (Cn) serotype A strain H99. Cn H99 is the most common Cn serotype to be isolated from the
environment and from clinical samples. Our model of immunocompromised mice that are pre-infected with Cn
H99 and received CD4+ T cell transfer show phenotypes reminiscent of those in C-IRIS human patients. Our
C-IRIS mice show an abundance of Cn H99 and CD4+ T cells in the brain, brain edema, brainstem neuronal
damage, and pulmonary dysfunction without lung histological damage. Therefore, we hypothesize that 1) Cn
H99 in the brain trigger CD4+ T migration to this organ, 2) brain-infiltrating CD4+ T and innate immune cells
damage brainstem neurons, which control respiratory function, directly and/or indirectly through edema, and
that 3) brainstem neuronal damage leads pulmonary dysfunction and eventual death. Our objective is to
identify the mechanisms underlying these key symptoms to pave the way toward the development of targeted
clinical therapeutics for C-IRIS. In Aim 1, we will identify the role of CD4+ T cell subtypes and innate immune
cells in the brain for C-IRIS development. In addition, we will identify the potential therapeutic strategies by
targeting CD4+ T cell and Cn H99 migration to the brain and upregulated co-stimulatory molecules. In Aim 2,
we will determine whether damage of lung-innervating neurons in the brainstem leads to pulmonary
dysfunction and death in C-IRIS mice. We will also identify the mechanism of brain neuronal damage in C-
IRIS mice by targeting four candidate pathways (brain edema, brain CD4+ T cell neurotoxicity, brain innate
immune cell neurotoxicity, and brain Cn H99). Completion of the proposed experiments will unravel how
immune system reconstitution induces detrimental signaling in C-IRIS and expand targeted
therapeutic
avenues
 for C-IRIS. Furthermore, this study will provide mechanistic insights into how adaptive immune
responses modulate brain neuronal function. Findings f...

## Key facts

- **NIH application ID:** 10201442
- **Project number:** 5R01AI136999-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Makoto Inoue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,976
- **Award type:** 5
- **Project period:** 2019-06-03 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201442

## Citation

> US National Institutes of Health, RePORTER application 10201442, Brain neuron damage-mediated respiratory failure and mortality during Cryptococcus-associated immune reconstitution inflammatory syndrome in mice (5R01AI136999-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201442. Licensed CC0.

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