The role of dermis resident macrophages and their interaction with neutrophils in the early establishment of Leishmania major infection transmitted by sand fly bite

There is substantial experimental evidence to indicate that  Leishmania  infections that are transmitted naturally by the bites of infected sand flies differ in fundamental ways from the inflammatory and immune reactions initiated by needle inocula.   We have used flow cytometry and intravital microscopy (IVM) to reveal the heterogeneity of sand fly transmission sites with respect to the subsets of phagocytes in the skin that harbor  L. major  within the first hours and days after infection.     By flow cytometry analysis, dermis resident macrophages (TRMs) were on average the predominant infected cell type at 1 hr and 24 hr.  By confocal IVM, the co-localization of  L. major  and neutrophils varied depending on the proximity of deposited parasites to the presumed site of vascular damage, defined by the highly localized swarming of neutrophils.    Some of the dermal TRMs could be visualized acquiring their infections via transfer from or efferocytosis of parasitized neutrophils, providing direct evidence for the “Trojan Horse” model.   The role of neutrophil engulfment by dermal TRMs and the involvement of the Tyro3/Axl/Mertk family of receptor tyrosine kinases in these interactions and in sustaining the anti-inflammatory program of dermal TRMs was supported by the effects observed in neutrophil depleted and in  Axl -/- Mertk -/-  mice. The  Axl -/- Mertk -/-  mice also displayed reduced parasite burdens but more severe pathology following  L. major  infection transmitted by sand fly bite.