Potential biomarkers of immune protection in human leishmaniasis

Abstract

Leishmaniasis is a vector-borne neglected tropical disease endemic in over 100 countries around the world. Available control measures are not always successful, therapeutic options are limited, and there is no vaccine available against human leishmaniasis, although several candidate antigens have been evaluated over the last decades. Plenty of studies have aimed to evaluate the immune response development and a diverse range of host immune factors have been described to be associated with protection or disease progression in leishmaniasis; however, to date, no comprehensive biomarker(s) have been identified as surrogate marker of protection or exacerbation, and lack of enough information remains a barrier for vaccine development. Most of the current understanding of the role of different markers of immune response in leishmaniasis has been collected from experimental animal models. Although the data generated from the animal models are crucial, it might not always be extrapolated to humans. Here, we briefly review the events during Leishmania invasion of host cells and the immune responses induced against Leishmania in animal models and humans and their potential role as a biomarker of protection against human leishmaniasis.

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

“…Anti-inflammatory (M2) macrophages show an IL-10 and IL-4 dominant response that can lead to decrease NO secretion (7,109,133). Furthermore, IL-10 can make macrophages refractory to IFN-g-mediated activation (99). In human VL, high IL-10 levels in blood and lesion tissue correlated with high parasitic load (134)(135)(136)(137)(138)(139).…”

“…In addition, salivary components induce a significant influx of macrophages in a CCL2/MCP-1 dependent mechanism in L. chagasi infection ( 97 ). Macrophage response to infection is dependent on the interplay of a) the surface molecules on the Leishmania parasites, such as glycoprotein-63 (gp63), lipophosphoglycan (LPG) and glycosylphosphatidylinositol (GPI); and b) the receptors which recognize them, such as Toll-like receptors (TLRs) ( 98 ) fibronectin, mannose, complement and Fc receptors ( Figure 3 ) ( 99 ). Binding of Leishmania to complement and Fc receptors slows down phagosome maturation ( 100 ) and induces IL-10 production ( 99 , 101 , 102 ).…”

“…Macrophage response to infection is dependent on the interplay of a) the surface molecules on the Leishmania parasites, such as glycoprotein-63 (gp63), lipophosphoglycan (LPG) and glycosylphosphatidylinositol (GPI); and b) the receptors which recognize them, such as Toll-like receptors (TLRs) ( 98 ) fibronectin, mannose, complement and Fc receptors ( Figure 3 ) ( 99 ). Binding of Leishmania to complement and Fc receptors slows down phagosome maturation ( 100 ) and induces IL-10 production ( 99 , 101 , 102 ). TLRs recognize Leishmania surface gp63 and activate the NF-κB pathway in macrophages ( Figure 3 ) ( 103 ).…”

“…Pro-inflammatory (M1) macrophages upregulate IL-12 and TNF-α expression, as well as ROS and RNS production, crucial to control Leishmania infection, as demonstrated in both mice and human models ( 111 , 125 , 126 ). Within this inflammatory microenvironment, IL-12 can upregulate iNOS and promote the development of IFN-γ-producing Th1 cells ( 99 ). IFN-γ then induces IL-12 and iNOS expression ( 99 ), which synthesizes high amounts of NO with leishmanicidal activities.…”

“…Within this inflammatory microenvironment, IL-12 can upregulate iNOS and promote the development of IFN-γ-producing Th1 cells ( 99 ). IFN-γ then induces IL-12 and iNOS expression ( 99 ), which synthesizes high amounts of NO with leishmanicidal activities. However, the signal transduction of both IL-12 and IFN-γ in macrophages is interrupted in Leishmania infections ( L. donovani, L. major , and L. mexicana) by inhibition of STAT-1 and STAT-4 phosphorylation ( 127 , 128 ).…”