Dr. Ute Frevert studied veterinary medicine at the Freie Universität Berlin, Berlin, Germany. She received her D.V.M. in 1982 and her Ph.D. in 1983. She was a postdoctoral fellow in the Department of Veterinary Biochemistry, Freie Universität Berlin, where she became Assistant Professor in 1988. In 1991, she completed her Habilitation. From 1991 to 1992, she was a Visiting Scholar at the Department of Pathology, NYU School of Medicine. In 1992, she was appointed Assistant Professor of the Department of Medical and Molecular Parasitology and since 2004, Dr. Frevert has been Associate Professor in the same Department.
Her laboratory focuses on cellular and molecular interactions between malaria parasites and the liver of the infected host. After injection into the skin by an infected mosquito, sporozoites enter dermal capillaries, use the bloodstream to travel to the liver, and develop inside hepatocytes to thousands of merozoites. To reach hepatocytes, sporozoites must traverse the layer of sinusoidal cells, which is composed of endothelia and Kupffer cells, the resident macrophages of the liver. Malaria sporozoites use their major surface proteins, the circumsporozoite protein (CSP) and the thrombospondin-related adhesive protein (TRAP) to interact with distinct cell type-specific surface proteoglycans expressed on hepatocytes, Kupffer cells, and stellate cells, but not from liver endothelia. According to the current model, the parasites are arrested in the sinusoid by binding to stellate cell-derived extracellular matrix proteoglycans, which are thought to protrude from the space of Disse across the sinusoidal fenestration into the sinusoidal lumen. Intravital studies documented that arrested sporozoites initially glide along the sinusoidal cell layer until they eventually encounter a Kupffer cell, which they use to traverse the sinusoidal cell barrier. Using two different Kupffer cell-deficient mouse models, Dr. Frevert’s group showed that these hepatic macrophages are obligatory for sporozoite infection of the liver. They also found that malaria sporozoites invade Kupffer cells actively by vacuole formation, avoid destruction by blocking lysosomal fusion of the vacuole, and safely pass exit these phagocytes towards the space of Disse. After migrating through several hepatocytes, the parasites eventually settle down in a final one for differentiation to merozoites.
Most recently, Dr. Frevert’s lab discovered another evasion mechanism of Plasmodium sporozoites: inhibition of the respiratory burst in Kupffer cells. To do this, the parasite CSP engages a multifunctional high-affinity scavenger receptor, the low density lipoprotein receptor-related protein (LRP), and Kupffer cell surface proteoglycans. This interaction induces an intracellular signaling cascade that prevents the assembly of the NADPH oxidase, the enzyme responsible for the production of reactive oxygen intermediates. It is thought that Kupffer cell deactivation allows sporozoites to enter the liver, develop inside hepatocytes in the immediate neighborhood to large schizonts, and differentiate to merozoites. Unpublished data indicate that sporozoites also modify the cytokine secretion pattern in Kupffer cells, suggesting that parasite survival in the liver is aided by the generation of an overall anti-inflammatory milieu.
Another focus of Dr. Frevert’s lab is on the release of Plasmodium merozoites into the blood. This parasite stage is sensitive to phagocytosis and has to avoid the gauntlet of Kupffer cells on the way out of the liver. They showed that mature liver schizonts bulge out into the sinusoidal lumen and release extrusomes, large bags containing hundreds of merozoites enclosed in membrane derived from the infected hepatocyte and therefore unrecognizable by the innate immune system of the host. This mechanism allows the parasites to safely exit the liver and infect erythrocytes at extrahepatic sites.
A new focus will be on the pathogenesis of cerebral malaria, a frequently fatal complication in particular young children. By imaging fluorescent Plasmodium parasites in a mouse model, Dr. Frevert aims to understand the mode of sequestration of malaria-infected erythrocytes and immune cells of the host in brain capillaries.
Overall, Dr. Frevert’s lab is interested in understanding the molecular basis of the various evasion mechanisms Plasmodium has acquired in the course of evolution that enable this deadly parasite to survive in the vertebrate host.