Determinants of Innate Immunity in Visceral Leishmaniasis and Their Implication in Vaccine Development

Abstract

Leishmaniasis is endemic to the tropical and subtropical regions of the world and is transmitted by the bite of an infected sand fly. The multifaceted interactions between Leishmania, the host innate immune cells, and the adaptive immunity determine the severity of pathogenesis and disease development. Leishmania parasites establish a chronic infection by subversion and attenuation of the microbicidal functions of phagocytic innate immune cells such as neutrophils, macrophages and dendritic cells (DCs). Other innate cells such as inflammatory monocytes, mast cells and NK cells, also contribute to resistance and/or susceptibility to Leishmania infection. In addition to the cytokine/chemokine signals from the innate immune cells, recent studies identified the subtle shifts in the metabolic pathways of the innate cells that activate distinct immune signal cascades. The nexus between metabolic pathways, epigenetic reprogramming and the immune signaling cascades that drive the divergent innate immune responses, remains to be fully understood in Leishmania pathogenesis. Further, development of safe and efficacious vaccines against Leishmaniasis requires a broader understanding of the early interactions between the parasites and innate immune cells. In this review we focus on the current understanding of the specific role of innate immune cells, the metabolomic and epigenetic reprogramming and immune regulation that occurs during visceral leishmaniasis, and the strategies used by the parasite to evade and modulate host immunity. We highlight how such pathways could be exploited in the development of safe and efficacious Leishmania vaccines.

Leishmania tarentolae as an Antigen Delivery Platform: Dendritic Cell Maturation after Infection with a Clone Engineered to Express the SARS-CoV-2 Spike Protein

“…When investigating vaccine vehicles or surrogate pathogens as antigens, it is therefore crucial to determine the response of DCs, which then orchestrate the successive phases of the immune reaction. Our results demonstrate that L. tarentolae is actually engulfed by monocyte-derived DCs, similarly to human and canine parasitic leishmaniae (e.g., [ 30 ]). However, while DC maturation is normally impaired by pathogenic leishmaniae (reviewed in [ 19 ]), we observed that L. tarentolae infection induces a proper activation of these cells, consistent with an increase in the expression of molecules involved in antigen presentation (HLA-DR II and CD83 expression) and CD4+ T cell stimulation (CD80 expression).…”

Impaired in vitro Interferon-γ production in patients with visceral leishmaniasis is improved by inhibition of PD1/PDL-1 ligation

“…Each subset can display different functions: broadly, classical monocytes exhibit strong phagocytosis abilities; intermediate monocytes are characterised by their abilities to induce T cell stimulation and high ROS production, as well as pro-angiogenic abilities; and non-classical monocytes are characterised by their patrolling behaviour of the vascular endothelium [ 20 ]. Importantly, the role of these different subsets in VL patients is poorly characterised [ 21 ].…”

“…Each subset can display different functions: broadly, classical monocytes exhibit strong phagocytosis abilities; intermediate monocytes are characterised by their abilities to induce T cell stimulation and high ROS production, as well as pro-angiogenic abilities; and non-classical monocytes are characterised by their patrolling behaviour of the vascular endothelium[20]. Importantly, the role of these different subsets in VL patients is poorly characterised[21].Here we tested whether the different monocyte subsets isolated from VL patients express PDL-1, and if so, if they express it differentially. Results presented inFig 2 and S1 Table show that directly ex vivo, monocytes in the PBMCs of VL patients express PDL1.…”

Metamorphosis of neutrophil transcriptional programme during Leishmania infection

“…Nevertheless, neutrophil-mediated protective immunity has been previously demonstrated in other vaccination regimens including modified vaccinia Ankara virus, poxvirus and live attenuated tuberculosis vaccine. 79 Recent evidence shows that human neutrophils can be polarized in vitro to an N1 or N2 phenotype, similar to polarization phenotypes described for macrophages. 80 Polarization of neutrophils to N1 was done under normoxia and in the presence of LPS, IFN-γ and IFN-β, whereas N2 polarized neutrophils were done under hypoxic F I G U R E 2 Overview of the heterogeneity of neutrophil subpopulations and its functional implications to Leishmania infection.…”

“…Moreover, these results suggest that phagocytosis is associated with a transcriptional programme devoted to antigen presentation, which is intriguing considering evidence that phagocytosis accelerates neutrophil apoptosis in vivo. Nevertheless, neutrophil‐mediated protective immunity has been previously demonstrated in other vaccination regimens including modified vaccinia Ankara virus, poxvirus and live attenuated tuberculosis vaccine 79 …”