Hepatic Inflammation Confers Protective Immunity Against Liver Stages of Malaria Parasite

Abstract

Deciphering the mechanisms by which Plasmodium parasites develop inside hepatocytes is an important step toward the understanding of malaria pathogenesis. We propose that the nature and the magnitude of the inflammatory response in the liver are key for the establishment of the infection. Here, we used mice deficient in the multidrug resistance-2 gene (Mdr2 −/−)-encoded phospholipid flippase leading to the development of liver inflammation. Infection of Mdr2 −/− mice with Plasmodium berghei ANKA (PbANKA) sporozoites (SPZ) resulted in the blockade of hepatic exo-erythrocytic forms (EEFs) with no further development into blood stage parasites. Interestingly, cultured primary hepatocytes from mutant and wild-type mice are equally effective in supporting EEF development. The abortive infection resulted in a long-lasting immunity in Mdr2 −/− mice against infectious SPZ where neutrophils and IL-6 appear as key effector components along with CD8 + and CD4 + effector and central memory T cells. Inflammation-induced breakdown of liver tolerance promotes anti-parasite immunity and provides new approaches for the design of effective vaccines against malaria disease.

Plasmodium-encoded murine IL-6 impairs liver stage infection and elicits long-lasting sterilizing immunity

“…Our laboratory has gathered during the last decade experimental evidence, using various murine models for malaria, that the IL-6 response is critical in controlling the parasite growth by generating an effective anti-parasite immune response [8, 9, 7, 10]. We decided to focus our study on the IL-6 cytokine for multiple reasons.…”

“…In a more recent work, we used mice deficient in the multidrug resistance-2 gene ( Mdr2 −/− ), which encodes the canalicular phospholipid flippase leading to a complete absence of phospholipids from bile, which were found to spontaneously develop liver injury with a typical inflammatory profile. In this model, we demonstrated that the intra-hepatocyte parasite development was impaired via an IL-6-dependent mechanism [10] and the abortive infection resulted in a long-lasting immunity in Mdr2 −/− mice against infectious SPZ. This IL-6-driven potent immune response was observed in the Mdr 2 −/- mouse model we reported recently where not only total CD8 + and CD4 + cells but also CD8 + and CD4 + tissue resident memory T cells were present at a significantly higher levels in SPZ challenged Mdr2 −/- mice [10].…”

“…In this model, we demonstrated that the intra-hepatocyte parasite development was impaired via an IL-6-dependent mechanism [10] and the abortive infection resulted in a long-lasting immunity in Mdr2 −/− mice against infectious SPZ. This IL-6-driven potent immune response was observed in the Mdr 2 −/- mouse model we reported recently where not only total CD8 + and CD4 + cells but also CD8 + and CD4 + tissue resident memory T cells were present at a significantly higher levels in SPZ challenged Mdr2 −/- mice [10].…”

“…), displaying an immune signature that comprised elevated IL-6 levels, activation of T and B cells, and antigen-specific IgG2c production [7]. During the last decade, in search of key mechanisms that determine the host inflammatory response, a set of host factors turned out to be critical for the control of malaria parasite development [8, 9, 7, 10]. Strikingly, the activation of the IL-6 signaling pathway occurred as a common theme, that apparently blocks parasite liver stage development, but more importantly allows the initiation of a robust and long-lasting anti-parasite immunity.…”

Tissue-resident memory T cells in chronic liver diseases: Phenotype, development and function

“…During infection of malaria, Plasmodium promotes the development of antigens-specific T RM cells ( 16 , 125 – 127 ). These T RM cells could mediate protective immune responses through killing infected cells by producing pro-inflammatory cytokines, such as IFN-γ and TNF-α ( 16 , 30 ). Additionally, T RM cell depletion abrogated an efficient immune response to a murine model of Plasmodium infection ( 31 ).Due to the protective immune response of T RM cells against malaria, vaccination strategies that maximize intrahepatic Plasmodium -specific T RM development have emerged ( 16 , 28 , 29 , 32 – 34 , 127 ).…”