Exposure to Leishmania braziliensis Triggers Neutrophil Activation and Apoptosis

Abstract

BackgroundNeutrophils are the first line of defense against invading pathogens and are rapidly recruited to the sites of Leishmania inoculation. During Leishmania braziliensis infection, depletion of inflammatory cells significantly increases the parasite load whereas co-inoculation of neutrophils plus L. braziliensis had an opposite effect. Moreover, the co-culture of infected macrophages and neutrophils also induced parasite killing leading us to ask how neutrophils alone respond to an L. braziliensis exposure. Herein we focused on understanding the interaction between neutrophils and L. braziliensis, exploring cell activation and apoptotic fate.Methods and FindingsInoculation of serum-opsonized L. braziliensis promastigotes in mice induced neutrophil accumulation in vivo, peaking at 24 h. In vitro, exposure of thyoglycollate-elicited inflammatory or bone marrow neutrophils to L. braziliensis modulated the expression of surface molecules such as CD18 and CD62L, and induced the oxidative burst. Using mCherry-expressing L. braziliensis, we determined that such effects were mainly observed in infected and not in bystander cells. Neutrophil activation following contact with L. braziliensis was also confirmed by the release of TNF-α and neutrophil elastase. Lastly, neutrophils infected with L. braziliensis but not with L. major displayed markers of early apoptosis.ConclusionsWe show that L. braziliensis induces neutrophil recruitment in vivo and that neutrophils exposed to the parasite in vitro respond through activation and release of inflammatory mediators. This outcome may impact on parasite elimination, particularly at the early stages of infection.

Infection and Activation of Human Neutrophils with Fluorescent Leishmania infantum

“…Despite observations of murine neutrophils to the contrary [21,23], our data also showed activation of “bystander” human PMNs in cultures containing L. infantum infected neutrophils. Bystander activation was not observed when fresh PMNs were incubated in conditioned medium from either L. infantum or L. infantum infected neutrophils.…”

“…They are the first cell to migrate to, and take up parasites at the site of in vivo infection with either L. major [5,18–20] or with L. infantum [6] species. Indeed, there appears to be distinct differences in the way various species of Leishmania result in activation and otherwise affect neutrophils [10,21–23]. In the context of disease progression, it has been suggested that, rather than control the infection, neutrophils exacerbate disease onset either by delaying apoptosis, by impairing activation of dendritic cells, or by serving as a vehicle route for silent entry of the parasite [4,24–26].…”

Leishmania braziliensis isolated from disseminated leishmaniasis patients downmodulate neutrophil function

“…The phagocyted microbes are destroyed by oxidative and nonoxidative mechanisms inside the neutrophils cytoplasm. The uptake of microbes induces the oxidative burst, increases reactive oxygen species (ROS) production and this leads to parasites clearance . Monocytes produce ROS after exposure to L. (V.) braziliensis, and in this cell, ROS contribute to control parasite multiplication .…”

“…The uptake of microbes induces the oxidative burst, increases reactive oxygen species (ROS) production and this leads to parasites clearance. 27,28 Monocytes produce ROS after exposure to L. (V.) braziliensis, and in this cell, ROS contribute to control parasite multiplication. 29,30 In contrast to monocytes, the ROS generated by infected neutrophils prevents parasite multiplication but did not decrease the number of intracellular amastigotes.…”

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

“…Interestingly, IL-1β has been shown to have variable roles in leishmaniasis, dependent upon the infective species [61–63]; notably, IL-1β was found to ameliorate L. (V.) braziliensis infection [63] but have an opposing effect for L. major , where MDSCs have been shown to exacerbate disease [62]. Further, the roles of PMNs in cutaneous leishmaniasis also appear to be variable and dependent on infecting species [61, 64, 65]; PMNs have been shown to enhance L. major infection and suppress L. (V.) braziliensis infection. It should be noted, however, that in these studies MDSCs and PMNs were not distinguished.…”