GalCer as receptor for pathogens

Glycosphingolipids like GalCer are used as cellular binding sites for a wide variety of pathogens, including viruses, bacteria, fungi and parasites (11). Namely, GalCer is recognized by the following: HIV-1, prions, Borrelia burgdorferi (the causative agent of Lyme disease; Borrelia burgdorferi bacteria are transmitted to humans by the bite of infected deer ticks and caused more than 23,000 infections in the United States in 2002.)

In addition to providing a wide variety of accessible sugar motifs, glycosphingolipids in lipid rafts are endocyted through a specific pathway. Indeed, internalization of ligands bound to lipid rafts is translocated to various cellular compartments (endoplasmic reticulum, nucleus, apical or basolateral membrane) but not to lysosomes. Thus, by chosing lipid rafts as a pathway of entry, microbes avoid potential lysosomal degradation. In other words, lipid rafts may be viewed as membrane-organelles shuttles that take the pathogens aboard on the cell surface and drive them to a protected intracellular niche (16).

Involvement of GalCer in HIV-1 enteropathy.

Malabsorption and diarrhea are common, serious problems in AIDS patients, and are in part due to the incompletely understood entity HIV enteropathy. The HIV-1 surface envelope glycoprotein gp120 binds to GalCer on the enterocyte cell surface. Then, the complex is delivered to a membrane protein called GPR-15/Bob. GalCer-contaninig lipid rafts allow the migration of HIV-1 on the cell surface until reaching GPR15/Bob. GPR15/Bob is a receptor with seven transmembrane domains coupled to G proteins. Thus, gp120-induced stimulation of this receptor results in a cascade of activation leading to a burst of intracellular calcium concentration, extensive microtubule depolymerization, an 80% decrease in intestinal barrier function and, and a 70% decrease in intestinal glucose absorption. These changes are also evidenced in the intestinal epithelium of AIDS patients suffering of enteropathy. Antibodies against GalCer (as well as anti-GPR15/Bob antibodies) block this suite of events and efficiently protect the cells from HIV-1 injury. As HIV-1 does not need to infect the intestinal cells to impair intestinal function, HIV-1 gp120 can be considered as a ‘virotoxin’ (17-19).