Leishmania infantum eukaryotic initiation factor 4A modulates in vitro functional activity of human neutrophils

Leishmaniases are a group of neglected tropical diseases caused by Leishmania parasites which virulence mainly relies on its modulation of the host immune response. Neutrophils, the first recruited innate immune cells at the site of infection, are key determinants of the early parasite control and disease outcome. However, their functional activation in response to parasite-derived molecules remains poorly understood. In this study, we investigated the effect of the Leishmania infantum Eukaryotic Initiation Factor 4A (LieIF), an excreted/secreted protein, on human neutrophils. Stimulation with recombinant LieIF protein induced a strong pro-inflammatory neutrophil response characterized by increased ROS production, degranulation, late apoptosis and enhanced secretion of IL-8, TNF-α, IL-1β and IL-6 cytokines associated with a reduced production of the anti-inflammatory cytokine TGF-β1. In contrast, IL-10, IFN-γ and IL-12p70 were not detected. Furthermore, LieIF induced the activation of p38 MAPK but had no effect on AKT, ERK1/2 and JNK kinases. Finally, inhibition of p38, using a specific pharmacological inhibitor, resulted in lesser production of TNF-α, IL-1β, IL-6 and IL-8 cytokines, confirming the functional contribution of the p38 MAPK in LieIF-induced neutrophil activation. These findings identify LieIF as a potent parasite-derived inflammatory protein that drives neutrophil activation via p38 kinase, highlighting its role in early innate immune response and its potential relevance for the development of novel therapeutic and vaccine strategies.