The effect of Saposin D on the anti-tuberculosis immune response in experimental tuberculosis infection

Abstract

Saposins (Sap) are a subgroup of glycoproteins belonging to the Saposin-Like Proteins family. They are generated by the proteolytic processing of the common precursor prosaposin. Saposins localize primarily in the lysosomes and are required for the catabolism of glycosphingolipids. Saposins are involved in the presentation of lipid mycobacterial antigens on CD1 molecules. SapD is the most abundant saposin in normal tissues, where its concentration is three times higher than that of other saposins. SapD promotes the hydrolysis of ceramide by acid ceramidase in vivo, as evidenced by the accumulation of -hydroxyl-ceramide in the kidneys and cerebellum of SapD-deficient mice. Accordingly, SapD-deficient animals show renal tubular degeneration and hydronephrosis, as well as progressive loss of Purkinje cells in the cerebellum, leading to ataxia. To date, no hereditary SapD deficiency has been identified in humans.Previously we had shown that macrophages derived from SAPD knockout mice suppress the growth of M. tuberculosis to a lesser extent than macrophages from wild-type mice. Moreover, compensation for the deficiency of SapD in knockout cells led to the restoration of their bactericidal function. Thus, SapD is an important component in the anti-TB immune response. However, it is not clear how SapD deficiency affects the in vivo antituberculosis immune response. In the model of experimental tuberculosis infection, it was shown that five weeks post infection the mycobacterial load in the lungs and spleens was significantly higher in SapD-ko mice than in wild-type mice. Analysis of the lung tissue cellular composition showed the differences between SapD-ko and B6 mice. Thus naive SapD-ko mice are characterized by a larger quantity of macrophages compared to B6 mice. It was also shown that five weeks after infection, SapD-ko mice differ from wild-type mice in a more pronounced neutrophilic infiltration of the lung tissue. A study of the propensity for apoptosis of cells in the lung tissue of SapD-ko mice showed that the content of apoptotic cells in the lungs of SapD knockout mice three weeks after infection was significantly higher than in wild-type B6 mice. Thus, SapD deficiency leads to a significant increase in inflammation during experimental tuberculosis infection, and also affects the predisposition of lung cells to apoptosis.