Scientific Publications by FDA Staff

J Immunol 2018 Jan 1;200(1):163-76

Live attenuated Leishmania donovani centrin gene-deleted parasites induce IL-23-dependent IL-17-protective immune response against visceral leishmaniasis in a murine model.

Banerjee A, Bhattacharya P, Dagur PK, Karmakar S, Ismail N, Joshi AB, Akue AD, KuKuruga M, McCoy JP Jr, Dey R, Nakhasi HL

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani (LdCen(-/-) ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen(-/-) -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen(-/-) parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen(-/-) Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen(-/-) -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-gamma-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-gamma abrogated LdCen(-/-) -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R(-/-) mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen(-/-) parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen(-/-) parasite-induced immunity and subsequent protection against visceral leishmaniasis.