Abstract
BackgroundLeishmaniasis is a neglected arthropod-borne disease that affects millions of people worldwide. Successful Leishmania infections require the mitigation of immune cell functions leading to parasite survival and proliferation. A large body of evidence highlights the involvement of neutrophils (PMNs) and dendritic cells (DCs) in the establishment of immunological responses against these parasites. However, few studies, contemplate to what extent these cells interact synergistically to constrain Leishmania infection.ObjectiveWe sought to investigate how PMNs and infected DCs interact in an in vitro model of Leishmania amazonensis infection.Material and MethodsBriefly, human PMNs and DCs were purified from the peripheral blood of healthy donors. Next, PMNs were activated with fibronectin and subsequently co-cultured with L. amazonensis-infected DCs.ResultsWe observed that L. amazonensis-infected DC exhibited lower rates of infection when co-cultivated with either resting or activated PMNs. Surprisingly, we found that the release of neutrophil enzymes was not involved in Leishmania killing. Next, we showed that the interaction between PMNs and infected-DCs was intermediated by DC-SIGN, further suggesting that parasite elimination occurs in a contact-dependent manner. Furthermore, we also observed that TNFα and ROS production was dependent on DC-SIGN-mediated contact, as well as parasite elimination is dependent on TNFα production in the co-culture. Finally, we observed that direct contact between PMNs and DCs are required to restore the expression of DC maturation molecules during L. amazonensis infection.ConclusionOur findings suggest that the engagement of direct contact between PMNs and L. amazonensis-infected DC via DC-SIGN is required for the production of inflammatory mediators with subsequent parasite elimination and DC maturation.
Highlights
Leishmaniasis is a neglected tropical disease caused by the infection of unicellular protozoans that belong to the genus Leishmania
We assessed whether human PMNs were able to influence the outcome of L. amazonensis infection in dendritic cells (DCs), and if such infection constrain was dependent on the state of neutrophil activation
DCs were infected with L. amazonensis for 24 hours and subsequently cultivated with either fibronectin-activated or resting PMNs for 12 hours as depicted in our experimental design scheme (Figure 1A)
Summary
A broad array of factors such as parasite species, host genetic and health status influence disease outcomes [7,8,9]. During the first stages of Leishmania transmission, neutrophils, a category of polymorphonuclear cell (PMNs), are rapidly recruited to the site of infection, being one of the first lineage of phagocytes to interact with these parasites [10]. A mounting body of evidence suggest that apart from directly promoting the elimination of pathogens, PMNs are able to influence the immunological functions of other leukocytes by promoting the migration of these cells to the site of infection, their activation, amplification of immunologic responses, and eventually pathogen elimination [11]. Few studies, contemplate to what extent these cells interact synergistically to constrain Leishmania infection
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