# Mechanisms of balancing the immune response during cryptococcal meningoencephalitis

> **NIH NIH R21** · UNIV OF MARYLAND, COLLEGE PARK · 2024 · $231,190

## Abstract

Project Summary
 Cryptococcosis is an opportunistic fungal infection that is caused by Cryptococcus neoformans and
often occurs in immunocompromised individuals including HIV/AIDS patients. Although the infection starts in
the lung via inhalation of the pathogenic fungus, the most common manifestation of cryptococcosis is
meningoencephalitis, which is a leading cause of mortality of HIV/AIDS patients and accounts for proximately
181,000 deaths worldwide annually. The high susceptibility of HIV/AIDS patients to C. neoformans infection is
attributed to their impaired cellular immunity. Consequently, C. neoformans proliferates in the brain without
control, leading to microbe-mediated brain damage. Antiretroviral therapy (ART) is a major advance in treating
HIV/AIDS patients by restoring cellular immune responses. However, after initiation of ART, up to 30% of
HIV/AIDS patients with cryptococcosis develop immune reconstitution inflammatory syndrome (IRIS), an
aberrant excessive immune response leading to host-mediated brain damage. Furthermore, post-infectious
inflammatory response syndrome (PIIRS) occurs frequently in HIV-negative patients with cryptococcal
meningoencephalitis. Therefore, a robust immune response is required for controlling the fungal growth;
however, the immune response must be tightly controlled to avoid host-mediated brain damage during
cryptococcal meningoencephalitis. A critical gap in our understanding remains: what are the mechanisms of
maintaining the balance between protective immune responses and immunopathology during cryptococcal
meningoencephalitis-associated IRIS? IL-10 is an important cytokine with anti-inflammatory properties and its
production was enhanced in the cerebrospinal fluid of HIV/AIDS patients during cryptococcal IRIS. Based on
clinical data and our preliminary murine studies, we hypothesize that IL-10 is critically involved in balancing the
immune responses during cryptococcal meningoencephalitis-associated IRIS. We will test the hypothesis in a
murine model that closely mimics cryptococcal IRIS of HIV/AIDS patients, by addressing the following aims: (1)
To determine the mechanism(s) involved in regulation of the immune responses by IL-10 during cryptococcal
meningoencephalitis-associated IRIS; (2) To determine the mechanism(s) involved in induction of IL-10 in the
brain during cryptococcal meningoencephalitis-associated IRIS. If successful, the findings from this study
would be fundamental for understanding regulation of immune balance during cryptococcal
meningoencephalitis-associated IRIS and provide scientific basis for targeting this cytokine aiming at
controlling deleterious inflammation in the brain of cryptococcal IRIS/AIDS patients.

## Key facts

- **NIH application ID:** 10877973
- **Project number:** 5R21AI177099-02
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Meiqing Shi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $231,190
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877973

## Citation

> US National Institutes of Health, RePORTER application 10877973, Mechanisms of balancing the immune response during cryptococcal meningoencephalitis (5R21AI177099-02). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10877973. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*