A mechanism of self-lipid endocytosis mediated by the receptor Mincle.

Cellular lipid uptake (through endocytosis) is a basic physiological process. Dysregulation of this process underlies the pathogenesis of diseases such as atherosclerosis, obesity, diabetes, and cancer. However, to date, only some mechanisms of lipid endocytosis have been discovered. Here, we show a previously unknown mechanism of lipid cargo uptake into cells mediated by the receptor Mincle. We found that the receptor Mincle, previously shown to be a pattern recognition receptor of the innate immune system, tightly binds a range of self-lipids. Moreover, we revealed the minimal molecular motif in lipids that is sufficient for Mincle recognition. Superresolution microscopy showed that Mincle forms vesicles in cytoplasm and colocalizes with added fluorescent lipids in endothelial cells but does not colocalize with either clathrin or caveolin-1, and the added lipids were predominantly incorporated in vesicles that expressed Mincle. Using a model of ganglioside GM3 uptake in brain vessel endothelial cells, we show that the knockout of Mincle led to a dramatic decrease in lipid endocytosis. Taken together, our results have revealed a fundamental lipid endocytosis pathway, which we call Mincle-mediated endocytosis (MiME), and indicate a prospective target for the treatment of disorders of lipid metabolism, which are rapidly increasing in prevalence.

Diagnostic Value of IgA Antibody Measurement in Tick-Borne Spotted Fever (Astrakhan Rickettsial Fever).

Tick-borne spotted fevers caused by Rickettsia occur worldwide. The symptoms of this bacterial infection are similar to those of viral infection, and thus, diagnostic accuracy has special clinical importance. One of the commonly used methods for the diagnosis of tick-borne spotted fever is enzyme-linked immunosorbent assay (ELISA), which is based on estimation of the presence of specific IgM antibodies in blood. However, IgA analysis has not been used for the diagnosis of rickettsial diseases thus far. We investigated the diagnostic value of IgA antibody determination using patient sera collected in the Astrakhan region of Russia, where an isolated site of Astrakhan rickettsial fever (ARF) caused by Rickettsia conorii subsp. caspia is located. Our investigation was performed on serum samples collected from 185 patients diagnosed with Astrakhan rickettsial fever from May to October 2019. Western blot analysis revealed that specific IgA antibodies, as well as IgM antibodies, from patient sera bind to high-molecular-weight pathogen proteins with similar masses. The obtained data show that the determination of IgM alone allows for serological confirmation of diagnosis in only 46.5% of cases but that the determination of both IgM and IgA increases this rate to 66.5%. Taken together, the findings show an important diagnostic value of IgA evaluation for tick-borne spotted fever rickettsiosis. IMPORTANCE Tick-borne spotted fevers caused by Rickettsia occur worldwide. The symptoms of this bacterial infection are similar to the symptoms of viral infection, and thus, diagnostic accuracy has special clinical importance. The most serious spotted fever group rickettsiosis is Rocky Mountain fever in the United States, which is caused by Rickettsia rickettsii, and disease complications can lead to hemiparesis, blindness, or amputation. Rickettsia conorii subsp. caspia causes a rickettsial spotted fever named Astrakhan rickettsial fever (ARF). One of the commonly used methods for the diagnosis of tick-borne spotted fevers is ELISA, which is based on estimation of the presence of specific IgM antibodies in blood, though IgA has not been used for the diagnosis of rickettsial diseases thus far. In this study, we showed that both IgA and IgM should be analyzed in the blood serum samples of patients to significantly enhance the accuracy of diagnostics of tick-borne spotted fever rickettsiosis.