6. LPS-induced FOXO3 and IKKε translocation in MDDCs and MEFs. Supporting Information Fig. 7. FOXO3a interacts with NF-κB, RelA, and IRF3. “
“Studies in animal models suggest that protection against malaria induced by intradermal (ID) administration of sporozoites is less effective compared to intravenous injection (IV). We investigated in a murine

model the protective efficacy and immune responses after ID or IV immunization of sporozoites. Mice were immunized via either IV or ID route with Plasmodium berghei sporozoites in combination with chloroquine GSK126 mouse treatment (CPS) (allowing full liver stage development) or by γ-radiation-attenuated sporozoites (RAS) (early liver stage arrest). While IV immunization with both RAS and CPS generated 90–100% protection, ID immunization resulted in reduced levels of protection with either immunization strategy in both Balb/cByJ (50%) and C57BL/6j mice (7–13%). Lower protection by ID routing associated with a 30-fold lower parasite liver load [P < 0.001 (χ2 = 49.08, d.f. = 1)] assessed by real-time in vivo imaging of bioluminescent APO866 concentration P. berghei parasites. Unlike IV, ID immunization did not result in expansion of CD8+ T cells with effector memory phenotype and showed lower IFNγ responses irrespective of the immunization regime. In conclusion, protection against

sporozoite infection is likely dependent on parasite liver infection and subsequently generated cellular immune responses. Attenuated whole malaria parasites are considered eligible candidates for a potentially successful vaccine (1,2). The approach is based on disruption of the Plasmodium parasite life cycle allowing the host to develop protective immunity in the absence of overt clinical disease (3). Whole parasite immunizations with radiation-attenuated sporozoites (RAS), or with sporozoites in combination with chloroquine chemo-prophylaxis (CPS), have been successfully conducted in mice and men resulting in complete protection (4–6). RAS arrest early in liver stage development (7), whereas CPS undergo full liver stage maturation releasing blood-stage

parasites Nintedanib price that are subsequently killed by chloroquine (4). While murine immunizations are generally performed by intravenous (IV) routing, alternative routes are required for sustainable clinical applications in humans. Immunity to malaria is known to comprise cellular and humoral responses (8). Various studies have report antibody responses during sporozoite immunization in mice, including RAS and CPS (9–11). Moreover, protective efficacy following IV immunizations in mice is attributed to liver CD8+ effector memory T cells and high levels of IFNγ production (12–15). However, lower levels of protection are induced following intradermal (ID) sporozoite immunization with either P. berghei genetically attenuated parasites (GAP) (16) or P. yoelii RAS (17). In a recent clinical study, subcutaneous or ID immunization with irradiated P.