Dysregulated lymphatic remodeling promotes immunopathology during non-healing cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is a vector borne disease that is endemic to tropical and sub-tropical regions of the world disproportionately affecting those of low socioeconomic status. The combined role of the parasite and the host's immune response in determining disease severity has made it challenging to discover new anti-leishmanial treatments. Previous work from our lab has established that the dermal lymphatic network is necessary for wound resolution in a model of healing CL with Leishmania major parasites. In CL, lymphatic remodeling allows for accumulated fluid to drain from the lesional site, thereby reducing disease severity. In this report, we present a new mechanism of immunopathology during non-healing CL brought about by 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) decreases from 6 to 12 weeks post infection (wpi), leading to a decrease over time in lymphatic vessel (LV) density. To induce lymphangiogenesis, exogenous vascular endothelial growth factor-C (VEGF-C) was administered by adenoviral delivery. VEGF-C increased LV dilation leading to reduced lesion sizes without altering parasite burdens, arguing targeting the lymphatics can alleviate immunopathology. Taken 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 during infection.