Role of sphingosine in fungal infection

Aspergillus and Candida species are opportunistic fungal pathogens that cause a wide variety of infections especially in immunocompromised patients. The high risk of invasive fungal infections within the raising population of immunocompromised individuals, along with the emergence of resistance to conventional antifungal agents, requires the development of new antifungal drugs.

Sphingosine has been implicated to play many roles in bacterial and viral infections. Thus, this study aims to identify the fungicidal activity of sphingosine and provide potential therapeutic strategies.

The killing rate of C. glabrata and A. fumigatus was investigated by kinetic growth assay, demonstrating that sphingosine kills 99.99% of the fungal cells in a time and dose dependent manner, representing the high efficiency of this new fungicidal agent.

In hosts with a susceptible immune system, Aspergillus conidia initially infect lungs, invade epithelial cells and develop an invasive aspergillosis with high lethality. In high-risk patients, prophylaxis against aspergillus is a valuable clinical strategy. For in vivo infection, a novel inhalational murine model of invasive pulmonary aspergillosis was developed and disease progression was monitored by histology, analysis of chemokine and cytokine responses in mouse lung, colony forming unit (CFU) and galactomannan immunoassay in bronchoalveolar lavage.

The results showed a significant reduction in CFU and galactomannan index in sphingosine treated-infected mice as compared to infected untreated mice. The histological evidence supports the effectiveness of the sphingosine in the control of invasive aspergillosis without cytotoxicity. Prophylactic treatment with nebulized sphingosine starting 3 days before Aspergillus infection for up to 14 days resulted in 100% survival and in resolution of the infection, whilst placebo inhaled mice had a lethality/reaching of the dropout burden of 50%.

Mechanistic studies showed that treatment with sphingosine leads to the early depolarization of the mitochondrial membrane potential (ΔΨm) and the generation of mitochondrial reactive oxygen species follow by release of cytochrome c, thereby initiating apoptosis.

Taken together, this study reveals the in vitro and in vivo efficacy of sphingosine and its mode of action against fungi via a direct effect on mitochondria. Moreover, because of its very good tolerability and ease of application, inhaled sphingosine should be further developed as a possible prophylactic agent against pulmonary aspergillosis among severely immunocompromised patient.


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