In Vivo Protection Provided by a Synthetic New Alpha-Galactosyl Ceramide Analog against Bacterial and Viral Infections in Murine Models

Abstract

Alpha-galactosyl ceramide (␣-GalCer) has been known to bind to the CD1d receptor on dendritic cells and activate invariant natural killer T (iNKT) cells, which subsequently secrete T-helper-cell 1 (Th1) and Th2 cytokines, which correlate with anti-infection activity and the prevention of autoimmune diseases, respectively. ␣-GalCer elicits the secretion of these two cytokines nonselectively, and thus, its effectiveness is limited by the opposing effects of the Th1 and Th2 cytokines. Reported here is the synthesis of a new ␣-GalCer analog (compound C34), based on the structure of CD1d, with a 4-(4-fluorophenoxy) phenyl undecanoyl modification of the N-acyl moiety of ␣-GalCer. Using several murine bacterial and viral infection models, we demonstrated that C34 has superior antibacterial and antiviral activities in comparison with those of several other Th1-selective glycolipids and that it is most effective by administering it to mice in a prophylactic manner before or shortly after infection.

Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy

“…These three compounds, especially C34, were more efficacious than C1 for the treatment of lung, melanoma, and breast cancers in mice. This is in line with our report that C34 also exerted better antimicrobial responses in mice (29). The Th1-polarized cytokine production and greater antimicrobial or anticancer activities elicited by the three phenyl glycolipids likely reflected the immune responses downstream of early activation of iNKTcells.…”

Sulfatide Attenuates Experimental Staphylococcus aureus Sepsis through a CD1d-Dependent Pathway

“…A significant proportion of hospital cases of sepsis is due to Gram-positive cocci, which induce a different inflammatory response from that of Gram-negative bacteria (25). The function of NKT cells in various milder infections is dependent on the type of infecting agent; thus, NKT cells play a beneficial role in some infections (26,27) and are detrimental in others (11). Therefore, observations from Gram-negative sepsis models cannot be extrapolated to S. aureus sepsis.…”

Synthesis of a-O- and a-S-Glycosphingolipids Related to Sphingomonous cell Wall Antigens Using Anomerisation

“…To this HBr 33% in AcOH (2 mL) was added and the reaction stirred at room temp for 3 h. The reaction was quenched with satd NaHCO 3) , washed with water, brine, dried over MgSO 4 …”

“…While monosaccharide and higher order saccharide (e.g., 3, Figure 1) antigens are known in these bacteria, it seems that the most potent stimulators of the iNKT cells are monosaccharides [7]. Such bacterial glycolipids have been shown to induce septic shock and bacterial clearance in infected mice, demonstrating that glycolipids stimulate an innate-type immune response to gram negative bacteria [2,3]. The Sphingomonadacae glycolipids contain glucuronic acid or galacturonic acid residues which are α-O-linked to sphinganine derivatives (Figure 1), and they are structurally related to α-GalCer 1.…”

“…The prototype antigen α-galactosylceramide (α-GalCer, 1) stimulates iNKT cells to kill tumour cells, release cytokines and activate other cells of the immune system in mice. Consequently there has been interest OPEN ACCESS in evaluating glycolipid antigens with potential as anti-infective agents & vaccine adjuvants [1][2][3][4][5][6][7][8][9][10], and clinical trials of some glycolipids have been undertaken [11] or their preclinical evaluation is advanced [12]. The cell walls of Sphingomonadacae bacteria present uronic acid containing glycosphingolipids such 2-4 [1][2][3]7] which stimulate iNKT cells.…”