Exploring the dermal immune and angiogenic responses to Schistosoma mansoni

Schistosoma mansoni is a parasitic helminth which gains access to the host’s vascular system by penetrating and migrating through the skin in search of a blood vessel. The aim of this thesis was to determine whether during this migration the schistosome cercariae induce blood vessel growth (angiogenesis). This was examined following both a single exposure to the parasite (1x) and four exposures (4x). After 4x infections it has been shown that the skin immune response is predominantly Th2 and may favour angiogenesis. Utilising both imaging and molecular techniques it was shown that the vasculature of the pinnae alters and pro-angiogenic growth factors are up –regulated after infection. This was exacerbated in the pinnae of 4x infected mice with a change in the predominant growth factors up regulated. The difference in growth factors between 1x infected and 4x infected mice was in part due to the influx of haematopoietic cells into the dermis (DEC). In the 4x infected pinnae the DEC were predominately eosinophils (45%) which expressed hepatocyte growth factor (HGF) and matrix metalloproteinases (MMPs). Macrophages in the 4x infected mice were alternatively activated (up –regulating Arginase-1 and Ym1) and producing pro- vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). These phenotypes were partially controlled by high levels of IL-10 in 4x pinnae, loss of which increased the expression of PlGF by macrophages. It was also shown that the cercarial secretions (0-3hrRP) have pro-angiogenic properties. Culture of human umbilical vein endothelial cells (HUVECs) with 0-3hRP induced cell proliferation and the formation of primitive branches in vitro. Additionally using the Matrigel plug method it was shown that 0-3hRP can induce the growth of new blood vessels in vivo. These results indicated that cercariae can directly induce blood vessel growth as well as altering the dermal innate immune response. This presents a potential therapeutic benefit in the treatment of non-healing wounds