The GUT microbiome-sphingosine 1-phosphate (S1P) axis in severe malaria

The National Institute of Allergy and Infectious Diseases awarded the Research Foundation of The City University of New York $235,500 on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the gut microbiome-sphingosine 1-phosphate (S1P) axis as a modulator of severe malaria.

The research will use murine models to determine the effect of gut microbiota composition on intestinal S1P levels and malaria outcomes, identify gut bacteria involved in S1P metabolism through click chemistry-based approaches and metagenomic profiling, and modulate S1P signaling through selective receptor and enzyme inhibitors to define its causal role in malaria pathogenesis. The work builds on preliminary evidence that oral vancomycin treatment, which depletes gut Bacteroides species, leads to elevated intestinal S1P levels and reduced Plasmodium yoelii burden, while S1P receptor inhibition results in uncontrolled severe hyperparasitemia and mortality in mice. The research proposes that Bacteroides species metabolize intestinal S1P, thereby reducing host S1P signaling and exacerbating malaria severity.

Performance occurs in New York, New York, with a period of performance from July 1, 2026, through June 30, 2028. The assistance type is a Project Grant.

Abstract

Malaria continues to impose a major global health burden, causing more than 200 million cases and 600,000 deaths annually, with children in sub-saharan africa being disproportionately affected. Despite current interventions, the growing resistance to antimalarial drugs and limited vaccine efficacy highlights the urgent need for novel strategies to prevent severe malaria. Emerging evidence implicates the GUT microbiome as a key determinant of malaria severity. Our recent studies demonstrated that GUT bacteroides species play a causal role in susceptibility to severe malaria anemia (SMA) in humans and severe hyperparasitemia in murine models. However, the mechanisms linking GUT bacteria to malaria pathogenesis remain unknown. This proposal introduces a new conceptual framework: the GUT microbiome-sphingosine 1-phosphate (S1P) axis as a modulator of malaria severity. S1P is a bioactive sphingolipid that regulates vascular integrity, lymphocyte trafficking, and inflammation. Our preliminary data show that oral vancomycin treatment, which depletes GUT bacteroides, leads to markedly elevated intestinal S1P levels and significantly reduced plasmodium yoelii 17XNL (P. Yoelii) burden, whereas oral inhibition of S1P receptors using fingolimod (FTY720) results in uncontrolled severe hyperparasitemia and mortality in mice. We hypothesize that bacteroides species metabolize intestinal S1P, thereby reducing host S1P signaling and exacerbating malaria severity. To test this hypothesis, we will use murine model to (1) determine the effect of GUT microbiota composition on intestinal S1P levels and malaria outcomes, (2) identify GUT bacteria involved in S1P metabolism using a click chemistry-based approach and metagenomic profiling, and (3) modulate S1P signaling through selective receptor and enzyme inhibitors to define its causal role in malaria pathogenesis. This highly innovative developmental research will establish a mechanistic link between microbial sphingolipid metabolism and host immune regulation during malaria, paving the way for microbiome-targeted therapeutic strategies to prevent severe malaria and offering broader insights into microbial control of host lipid signaling and inflammation-driven diseases.