Leishmania killing is mediated by IFN-γ-activated macrophages, but IFN-γ production and macrophage activation are insufficient to control L. braziliensis infection. In American tegumentary leishmaniasis (ATL), pathology results from an exaggerated inflammatory response. This report presents an overview of our contributions regarding ATL pathogenesis, highlighting future directions to improve the management of L. braziliensis infection. Monocytes and lymphocytes from individuals exposed to L. braziliensis but who do not develop CL, i.e., subclinical infection (SC), exhibit lower respiratory burst and IFN-γ production, yet more efficiently kill L. braziliensis. As vaccines aimed at inducing IL-12 and IFN-γ do not sufficiently prevent CL, the elucidation of how subjects with SC infection kill Leishmania may lead to new approaches to controlling ATL. While inflammation arising from the recruitment of inflammatory cells via chemokines induced by IFN-γ and TNF or IL-17 is observed and contributes to pathology, cytotoxic CD8+ T cells and NK cells play a key role in the pathogenesis of L. braziliensis infection. The increased transcription of genes related to inflammation and cytotoxicity, e.g., granzyme A, granzyme B, NLRP3 and IL-1β, has been documented in CL tissue samples. The release of products by killed cells leads to NLRP3 inflammasome activation, IL-1β production and additional damage to skin and mucosal tissues. The use of drugs that downmodulate the inflammatory response in combination with chemotherapy improves the ATL cure rate and decreases healing time.
Keywords: American tegumentary leishmaniasis (ATL); Leishmania braziliensis; host parasite infection; leishmaniasis; pathology; protection.