Impaired lymphatic remodeling leads to immunopathology during non-healing cutaneous leishmaniasis 4376

Abstract Description Cutaneous leishmaniasis (CL) is a vector-borne parasitic disease that is endemic to tropical and sub-tropical regions of the world, disproportionately affecting those of low socioeconomic status. Previous work from our lab has established that the dermal lymphatic network is necessary for wound resolution in a model of healing CL with L. major parasites. Here, we present a new mechanism of immunopathology during non-healing CL following L. amazonensis infection. We show non-healing CL develops alongside an accumulation of cells and fluid in the skin, resulting in chronic inflammation. Lymphatic remodeling is attenuated during the chronic phase of L. amazonensis infection. Moreover, the percentage of proliferating lymphatic endothelial cells (LECs) declines from 6 to 12 weeks post infection (wpi), leading to a decrease over time in lymphatic vessel (LV) density and a decline in lymphatic drainage. To induce lymphangiogenesis, exogenous vascular endothelial growth factor-C (VEGF-C) was administered by adenoviral delivery. VEGF-C increased LV dilation leading to smaller lesion sizes without altering parasite burdens. Together, these results show impaired lymphatic function contributes to non-healing disease due to L. amazonensis infection and the lymphatics can be targeted to decrease inflammation in the skin. In CL, lymphatic remodeling allows for accumulated fluid to drain from the lesional site, thereby reducing disease severity. Funding Sources NIGMS P20-GM103625, NCATS TL1 TR003109 and UL1 TR003107, NIH T32 GM106999. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)