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Background  Visceral leishmaniasis (VL) caused by the protozoan parasite  Leishmania donovani  causes severe disease. Age appears to be critical in determining the clinical outcome of VL and at present there is no effective vaccine available against VL for any age group. Previously, we showed that genetically modified live attenuated  L .  donovani  parasites ( LdCen-/- ) induced a strong protective innate and adaptive immune response in young mice. In this study we analyzed  LdCen-/-  parasite mediated modulation of innate and adaptive immune response in aged mice (18 months) and compared to young (2 months) mice.    Methodology  Analysis of innate immune response in bone marrow derived dendritic cells (BMDCs) from both young and aged mice upon infection with  LdCen-/-  parasites, showed significant enhancement of innate effector responses, which consequently augmented CD4 +  Th1 cell effector function compared to  LdWT  infected BMDCs  in vitro . Similarly, parasitized splenic dendritic cells from  LdCen-/-  infected young and aged mice also revealed induction of proinflammatory cytokines (IL-12, IL-6, IFN-γ and TNF) and subsequent down regulation of anti-inflammatory cytokine (IL-10) genes compared to  LdWT  infected mice. We also evaluated  in vivo  protection of the  LdCen-/-  immunized young and aged mice against virulent  L .  donovani  challenge. Immunization with  LdCen-/-  induced higher IgG2a antibodies, lymphoproliferative response, pro- and anti-inflammatory cytokine responses and stimulated splenocytes for heightened leishmanicidal activity associated with nitric oxide production in young and aged mice. Furthermore, upon virulent  L .  donovani  challenge,  LdCen-/-  immunized mice from both age groups displayed multifunctional Th1-type CD4 and cytotoxic CD8 T cells correlating to a significantly reduced parasite burden in the spleen and liver compared to naïve mice. It is interesting to note that even though there was no difference in the  LdCen-/-  induced innate response in dendritic cells between aged and young mice; the adaptive response specifically in terms of T cell and B cell activation in aged animals was reduced compared to young mice which correlated with less protection in old mice compared to young mice.    Conclusions  Taken together,  LdCen-/-  immunization induced a significant but diminished host protective response in aged mice after challenge with virulent  L .  donovani  parasites compared to young mice.

plos neglected tropical diseases

Live Attenuated Leishmania donovani Centrin Knock Out Parasites Generate Non-inferior Protective Immune Response in Aged Mice against Visceral Leishmaniasis