# Sphingosine-1-phosphate and cryptococcosis

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $498,277

## Abstract

ABSTRACT
 The goal of this project is to study the role of the host SK1-S1P pathway in controlling the infection by
Cryptococcus neoformans (Cn). In previous studies, we identified that the host sphingosine kinase 1 (SK1) and its
product sphingosine-1-phosphate (S1P) are critical for the formation of the lung granuloma against Cn.1-3 Our
studies in mice are supported by the observation that patients treated with FTY720 (Fingolimod) for multiple
sclerosis4 (MS) developed cryptococcosis.5-9 When we administered FTY720 to our model of mouse granuloma, Cn
lung infection reactivated and fungal cells disseminated from the lung to the brain tissue, eventually killing the
animals. Intriguingly, this effect was not observed with BAF312 or AUY954 treatment. FTY720 is a sphingosine
analog that, once phosphorylated, mimics S1P and binds to S1P receptors S1Pr1, S1Pr3 and S1Pr510 whereas the
un-phosphorylated form of BAF312 or AUY954 binds to S1Pr1 and S1Pr5,11 or only to S1Pr1,12 respectively. These
results suggest that SK1-S1P may regulate the containment of Cn cells within the lung granuloma through the
inhibition of a specific S1P receptor(s), such as S1Pr3, as this is one of the receptors targeted by FTY720 but not
by the other compounds. Because these drugs all induce a severe lymphopenia by blocking the egress of
lymphocytes from lymph nodes,13-15 our studies also suggest that lymphopenia may not be sufficient for Cn infection
to reactivate.
 Based on these findings, we hypothesize that the action of S1P on S1Pr regulates the host cellular
immunity against Cn and that blocking S1Pr3 is detrimental for the host and may lead to reactivation of
cryptococcosis during lymphopenia. Thus we will: 1) determine how SK1-S1P regulates the formation of Cn
granuloma; and 2) define the host immune response controlled by SK1-S1P that protects against the
reactivation of Cn granuloma.

## Key facts

- **NIH application ID:** 9851334
- **Project number:** 5R01AI136934-03
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Maurizio Del Poeta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $498,277
- **Award type:** 5
- **Project period:** 2018-02-16 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851334

## Citation

> US National Institutes of Health, RePORTER application 9851334, Sphingosine-1-phosphate and cryptococcosis (5R01AI136934-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9851334. Licensed CC0.

---

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