The goal of this project is to study the role and mechanisms by which host sphingolipids are involved in controlling the infection caused by the pathogenic fungus Cryptococcus neoformans (Cn). A rapidly emerging area of research is the study of the role of sphingolipids in the regulation of infectious diseases (Reviewed in1). Although some sphingolipids have been linked to antibacterial activity of phagocytic cells,2,3 very little is known about the role of host sphingolipids against fungal infections. One of the host sphingolipid-metabolizing enzymes shown to regulate immune responses is sphingomyelin synthase (SMS), encoded by the SMS1 and SMS2 genes.4-6 SMS transfers a choline phosphate moiety from phosphatidylcholine (PC) to ceramide, therefore producing sphingomyelin (SM) and diacylglycerol (DAG).7-9 Very interestingly, the lipids regulated by SMS have been implicated in the activation of pro-inflammatory responses, suggesting that the regulation of SMS activity in immune cells may assume a critical role in controlling infections. In our preliminary and published studies10,11 we found that: 1) inhibition of SMS activity profoundly impairs the ability of phagocytic cells to kil Cn cells by affecting extracellular killing in absence of phagocytosis; 2) SMS regulates production of DAG at the Golgi; 3) DAG produced at the Golgi by SMS regulates protein secretion via activation of protein kinase D (PKD); 4) inhibition of SMS or PKD blocks extracellular killing of Cn and peptide secretion (such as defensins) by neutrophils; and 5) neutropenia significantly exacerbates Cn infection. Based on these observations, we hypothesize that SMS activity plays a key role in controlling the extracellular killing of neutrophils through the regulation of a DAG-PKD-mediated secretion pathway (Figure 1). Thus, we propose the following aims: 1) To establish the role of SMS against Cn; and 2) To determine the mechanism by which SMS regulates Cn killing. The studies proposed in this applications are significant and novel at different levels: i) they will establish novel animal models for the study of fungal infection that are more clinically relevant to the human infection than current models; ii) they will define the role of phagocytes in the host response to fungal infections; and iii) they will identify novel regulators of the phagocytes' response against the infection which can be engineered to boost the host immune system.

Public Health Relevance

Fungal infections have dramatically increased during the last decade afflicting both immunodeficient and immunocompetent individuals including military personnel. This proposal focuses on a better understanding of host resistance and susceptibility with important implications for the developing of new therapeutic strategies.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Infectious Diseases B (INFB)
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Northport VA Medical Center
United States
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Rizzo, Juliana; Colombo, Ana C; Zamith-Miranda, Daniel et al. (2018) The putative flippase Apt1 is required for intracellular membrane architecture and biosynthesis of polysaccharide and lipids in Cryptococcus neoformans. Biochim Biophys Acta Mol Cell Res 1865:532-541
Fernandes, Caroline Mota; Goldman, Gustavo H; Del Poeta, Maurizio (2018) Biological Roles Played by Sphingolipids in Dimorphic and Filamentous Fungi. MBio 9:
Bryan, Arielle M; Del Poeta, Maurizio (2018) Sphingosine-1-phosphate receptors and innate immunity. Cell Microbiol 20:e12836
Raj, Shriya; Nazemidashtarjandi, Saeed; Kim, Jihyun et al. (2017) Changes in glucosylceramide structure affect virulence and membrane biophysical properties of Cryptococcus neoformans. Biochim Biophys Acta Biomembr 1859:2224-2233
Bouklas, Tejas; Alonso-Crisóstomo, Luz; Székely Jr, Tamás et al. (2017) Generational distribution of a Candida glabrata population: Resilient old cells prevail, while younger cells dominate in the vulnerable host. PLoS Pathog 13:e1006355
Singh, Ashutosh; MacKenzie, Andrew; Girnun, Geoffrey et al. (2017) Analysis of sphingolipids, sterols, and phospholipids in human pathogenic Cryptococcus strains. J Lipid Res 58:2017-2036
Kim, Ji Hyun; Singh, Ashutosh; Del Poeta, Maurizio et al. (2017) The effect of sterol structure upon clathrin-mediated and clathrin-independent endocytosis. J Cell Sci 130:2682-2695
Mor, Visesato; Farnoud, Amir M; Singh, Ashutosh et al. (2016) Glucosylceramide Administration as a Vaccination Strategy in Mouse Models of Cryptococcosis. PLoS One 11:e0153853
Bryan, Arielle M; Del Poeta, Maurizio (2016) Secretory aspartyl proteinases induce neutrophil chemotaxis in vivo. Virulence 7:737-9
Rella, Antonella; Farnoud, Amir M; Del Poeta, Maurizio (2016) Plasma membrane lipids and their role in fungal virulence. Prog Lipid Res 61:63-72

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