Abstract
BackgroundThere are no effective vaccines for visceral leishmaniasis (VL), a neglected parasitic disease second only to malaria in global mortality. We previously identified 14 protective candidates in a screen of 100 Leishmania antigens as DNA vaccines in mice. Here we employ whole blood assays to evaluate human cytokine responses to 11 of these antigens, in comparison to known defined and crude antigen preparations.MethodsWhole blood assays were employed to measure IFN-γ, TNF-α and IL-10 responses to peptide pools of the novel antigens R71, Q51, L37, N52, L302.06, J89, M18, J41, M22, M63, M57, as well as to recombinant proteins of tryparedoxin peroxidase (TRYP), Leishmania homolog of the receptor for activated C kinase (LACK) and to crude soluble Leishmania antigen (SLA), in Indian patients with active (n = 8) or cured (n = 16) VL, and in modified Quantiferon positive (EHC+ve, n = 20) or modified Quantiferon negative (EHC−ve, n = 9) endemic healthy controls (EHC).ResultsActive VL, cured VL and EHC+ve groups showed elevated SLA-specific IFN-γ, but only active VL patients produced IL-10 and EHC+ve did not make TNF-α. IFN-γ to IL-10 and TNF-α to IL-10 ratios in response to TRYP and LACK antigens were higher in cured VL and EHC+ve exposed individuals compared to active VL. Five of the eleven novel candidates (R71, L37, N52, J41, and M22) elicited IFN-γ and TNF-α, but not IL-10, responses in cured VL (55–87.5% responders) and EHC+ve (40–65% responders) subjects.ConclusionsOur results are consistent with an important balance between pro-inflammatory IFNγ and TNFγ cytokine responses and anti-inflammatory IL-10 in determining outcome of VL in India, as highlighted by response to both crude and defined protein antigens. Importantly, cured VL patients and endemic Quantiferon positive individuals recognise 5 novel vaccine candidate antigens, confirming our recent data for L. chagasi in Brazil, and their potential as cross-species vaccine candidates.
Highlights
Visceral leishmaniasis (VL), known as kala-azar, is a potentially fatal disease caused by obligate intracellular parasites of the Leishmania donovani species complex
soluble Leishmania antigen (SLA) cytokine responses correlate with disease status To investigate antigen specific production of IFN-c, tumour necrosis factor-a (TNF-a) and IL-10 cytokines, diluted whole blood from different patient groups was initially stimulated with SLA from an Indian L. donovani strain
Results for active visceral leishmaniasis (VL), cured VL and endemic healthy controls (EHC)+ve groups are summarised in figures 3 (TRYP) and 4 (LACK)
Summary
Visceral leishmaniasis (VL), known as kala-azar, is a potentially fatal disease caused by obligate intracellular parasites of the Leishmania donovani species complex. A small percentage of infected individuals develop severe disease [7,8], and patients who recover from VL display resistance to reinfection [5]. This suggests the development of protective immunity and provides a rational basis for the development of vaccines that impart potent cell-mediated immune responses. There are no effective vaccines for visceral leishmaniasis (VL), a neglected parasitic disease second only to malaria in global mortality. We employ whole blood assays to evaluate human cytokine responses to 11 of these antigens, in comparison to known defined and crude antigen preparations
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