# Immunoregulatory Mechanisms to Combat CNS Pathology During Infection

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Objectives: Cryptococcus neoformans is the most important fungal pathogen causing CNS-related mortality
and morbidity world-wide. Although CM is generally viewed as a disease caused by weak immunity, evidence
accumulates that exuberant host immune responses significantly contribute to the pathogenesis of CM. To this
end, we developed a murine model of CM that reproduces major features of inflammatory CNS injury in CM
patients and found that the exuberant CNS inflammation, driven by ultra Th1-polarized T cells and
inflammatory monocytes, promotes severe immunopathology with neurological deterioration.
Regulatory T cells (Tregs) are the crucial component of this immunoregulatory network, and their dysfunction
is linked to inflammatory complications of CM in human patients. Our published and unpublished Preliminary
Data now support that Treg play crucial roles in limiting the pathological inflammation within the
Cryptococcus-infected CNS. Our preliminary data further show that Treg specifically express chemokine
receptor CCR8 and that Treg-recruitment kinetics is paralleled by the upregulation of CCR8 ligand chemokine
CCL1, supporting the importance of the CCL1/CCR8 axis in mediating CNS migration of Treg. We show that
among all cellular populations within the CNS, Treg are the major, if not sole producer of the immune-
regulatory cytokine IL-10 and Amphiregulin (Areg), factor known to promote wound healing and tissue repair.
Hypothesis: Hypothesis that CCL1/CCR8-axis-recruited Treg protect against severe CNS damage and
subsequent mortality in mice with CM via production of IL-10 and Areg and that Treg-based immunotherapies
will reduce morbidity and mortality in mice with CM. To test distinct parts of this hypothesis we will:
Aim 1. To demonstrate that CCR8-recruited Treg protect the brain from inflammatory pathology in CM
1.a. determine if Treg limit excessive CNS inflammation during CM, especially reducing pathological elements
of the CNS host response
1.b. define whether and how Treg reduce neuropathological processes in the CM-afflicted brain
1.c. demonstrate the dependence of the CCR8 axis for CNS Treg accumulation and their function during CM.
Aim 2: To define the therapeutic effects of Treg in CM
2.a. demonstrate that Treg enhancement by IL-2 immune complex therapy protects mice from fatal CM
pathology
2.b. determine if CCR8+ versus CCR8- Treg adoptive transfer protects mice from fatal CM pathology
Aim 3: To determine the mechanisms by which Treg limit CNS inflammation and promote
neurological repair during CM
3.a. determine if Treg-derived IL-10 is required for limiting pathological CNS inflammation during CM
3.b. define whether Treg-derived Areg promotes neurological repair during CM.
Research Plan and Methods: This proposal will use our established mouse model of CM, which accurately
recapitulates severe paradoxical immune responses experienced by patients with C. neoformans CNS infection.
We will manipulate Treg system (remove or expand T...

## Key facts

- **NIH application ID:** 10720879
- **Project number:** 5I01BX000656-14
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Michal A Olszewski
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2010-04-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10720879

## Citation

> US National Institutes of Health, RePORTER application 10720879, Immunoregulatory Mechanisms to Combat CNS Pathology During Infection (5I01BX000656-14). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10720879. Licensed CC0.

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