Neutrophil interactions with Leishmania amastigotes: implications for chronic leishmaniasis


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Leishmaniasis is a neglected tropical disease responsible for considerable morbidity and mortality in the developing world. The immune response against Leishmania parasites must be fine-tuned to promote pathogen clearance without triggering excess inflammation, and this requires the concerted efforts of numerous innate and adaptive immune cell types. Neutrophils are a prevalent component of the inflammatory infiltrate during the acute phase (caused by promastigotes) and chronic phase (caused by amastigotes) of leishmaniasis, but the role of these cells in the anti-parasite immune response and disease pathogenesis is incompletely characterized at this time. The work presented in this dissertation is intended to bridge a gap in our understanding of interactions between Leishmania parasites (especially the amastigote stage) and neutrophils. First, we found that neutrophils readily internalize Leishmania amazonensis promastigotes and amastigotes and respond to infection through CD11b upregulation and oxidative burst. However, cytokine release and the ability of neutrophils to clear internalized parasites differed depending on the infecting parasite stage. Specifically, neutrophils efficiently killed promastigotes and responded to infection by releasing pro-inflammatory TNF-α. In contrast, neutrophils were unable to effectively kill L. amazonensis amastigotes and responded to infection by releasing anti-inflammatory IL-10. To determine whether amastigote resistance to neutrophil microbicidal mechanisms is conserved among Leishmania species, we compared neutrophil responses to amastigotes of L. amazonensis and L. braziliensis. We found that L. braziliensis is a significantly more potent trigger for neutrophil activation, oxidative burst, degranulation, and cytokine release when compared to L. amazonensis. Heightened neutrophil activation in response to L. braziliensis infection strongly corresponded to an enhanced ability of neutrophils to kill this parasite species. Finally, to better understand the role of neutrophils in a model of chronic cutaneous leishmaniasis, we treated L. amazonensis-infected mice with anti-neutrophil antibodies between weeks 4 and 10 post-infection. We observed that anti-neutrophil treatment exacerbated lesion progression in infected mice. Collectively, these findings suggest that neutrophils may play a previously-underappreciated role in the chronic phase of cutaneous leishmaniasis.



Leishmania, amastigote, promastigote, neutrophil, oxidative burst, cytokine, degranulation, NETosis