# Role of host sphingolipids against fungal infections

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2022 · —

## Abstract

ABSTRACT
 The goal of this project is to study the role and mechanisms by which sphingomyelin synthases (Sms1 and Sms2)
are involved in controlling the infection caused by the pathogenic fungus Cryptococcus neoformans (Cn).
 Our laboratory has pioneered studies dealing with the role of fungal sphingolipids in the regulation of infectious
diseases. In addition to studying fungal sphingolipids, we have recently discovered that certain host sphingolipids play
a key role in controlling the immune response against the human fungal pathogen Cn. One of the host sphingolipid
shown to regulate immune responses is sphingomyelin (SM) produced by sphingomyelin synthase (SMS), encoded by
the SMS1 and SMS2 genes.1,2 SMS transfers a choline phosphate moiety from phosphatidylcholine (PC) to ceramide,
producing SM and diacylglycerol (DAG) (Fig. 1).3,4 These lipids have been implicated in many cellular functions including
the activation of pro-inflammatory responses,5 suggesting that the regulation of SMS activity in immune cells may
assume a critical role in controlling infections. In fact, we have shown previously that the DAG produced by SMS
mediates the in vitro extracellular killing of Cn by phagocytic cells possibly through a protein kinase D (PKD) dependent
mechanism, and the SMS-DAG-PKD signaling pathway mediates the secretion of antimicrobial peptides by phagocytic
cells, particularly defensins (§ Progress Report, new Fig. 9, and6,7).
 Very intriguingly, our current studies also revealed a key role for SM in the regulation of cholesterol-rich membrane
rafts in macrophages. We found that depletion of SM in the outer membrane of macrophages dramatically decreases
phagocytosis (Figs. 3 and 5) and displaces the Fcg receptor (FcgR) from a punctuated, clustered to a diffused and
homogeneous distribution (Fig. 7). This phenomenon was validated when cholesterol was depleted (Fig. 7),
corroborating the association of the FcgR with lipid rafts. The resulting effect of these depletions is a significant decrease
of antibody-mediated phagocytosis of Cn (Figs. 3, 4 and 5).
 Importantly, the displacement of the FcgR was also observed in alveolar macrophages isolated from mice lacking
Sms1 (sms1-/-) or Sms2 (sms2-/-), which also showed a decrease of antibody-mediated phagocytosis (new Fig. 12).
Taken together, these results suggest that SMS regulates the internalization of Cn cells by macrophages through the
production of SM, which, at the plasma membrane, stabilizes cholesterol-rich lipid rafts (new Fig. 8) for anchoring the
FcgR.
 Deletion of Sms1 (sms1-/-) or Sms2 (sms2-/-) renders the animals significantly hypersusceptible to Cn infection
(Fig. 10). Upon inhalation, Cn cells are rapidly replicating in the lung and quickly disseminating to the brain of sms1-/-
or sms2-/- mice (new Fig. 11). Preliminary flow cytometry shows a different immuno cellular composition in sms2-/-
compared to WT lungs (new Fig. 15), and the sms2-/- mice cannot form an efficient lung granuloma...

## Key facts

- **NIH application ID:** 10427149
- **Project number:** 5I01BX002624-07
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** Maurizio Del Poeta
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2015-10-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427149

## Citation

> US National Institutes of Health, RePORTER application 10427149, Role of host sphingolipids against fungal infections (5I01BX002624-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10427149. Licensed CC0.

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