The Role of Sphingolipids on Innate Immunity to Intestinal Salmonella Infection

Abstract

Salmonella spp. remains a major public health problem for the whole world. To reduce the use of antimicrobial agents and drug-resistant Salmonella, a better strategy is to explore alternative therapy rather than to discover another antibiotic. Sphingolipid- and cholesterol-enriched lipid microdomains attract signaling proteins and orchestrate them toward cell signaling and membrane trafficking pathways. Recent studies have highlighted the crucial role of sphingolipids in the innate immunity against infecting pathogens. It is therefore mandatory to exploit the role of the membrane sphingolipids in the innate immunity of intestinal epithelia infected by this pathogen. In the present review, we focus on the role of sphingolipids in the innate immunity of intestinal epithelia against Salmonella infection, including adhesion, autophagy, bactericidal effect, barrier function, membrane trafficking, cytokine and antimicrobial peptide expression. The intervention of sphingolipid-enhanced foods to make our life healthy or pharmacological agents regulating sphingolipids is provided at the end.

Keywords: Salmonella; innate immunity; intestine epithelia; sphingolipids.

Figure 1

The role of sphingolipids on innate immunity of intestinal epithelial cells against Salmonella infection. After Salmonella infection, intestinal epithelial cells mediate innate immunity against pathogenic bacteria. The reported mechanisms were summarised in this cartoon module. (1) Salmonella binds to the glycosphingolipids (e.g., glucosylceramide) of the host, leading to adhesion of the bacteria; (2) Sphingomyelin is required for membranous translocation of RhoA and Cdc42, resulting in caveolar endocytosis. (3) However, activation of Rac1 and Cdc42 is critical for the disruption of the barrier integrity by S. typhimurium via altered localization of tight and adherens junction proteins; (4) One of the Salmonella effector proteins, SigD/SopB, is essential for the establishment of the Salmonella-containing vacuoles (SCVs) which promotes intracellular survival of the bacteria. Disruption of the SCV then leads to increased replication of S. typhimurium in the cytosol of the epithelial cells; (5) Membrane sphingolipids may be involved in the Salmonella-induced cellular autophagy of damaged SCVs, because the suppression of phosphorylated Akt may contribute to apoptosis of the SCVs, leading to their damage, which is directed for autophagic clearance; (6) MYO1C regulates lipid raft recycling to the cell surface to deliver signaling components and the extra membrane essential for cell surface expansion and remodeling for controlling cell spreading, migration, and Salmonella invasion; (7) The de novo synthesis of sphingolipids may enhance IL-8 production in Salmonella-infected IECs; (8) In contrast, sphingolipids recruiting NOD2 and Atg16L1 into the plasma membrane of IECs infected by Salmonella contribute to the enhanced autophagic clearance and hBD-2-killing of the invading pathogen.