Towards the establishment of a permanent European Virtual Institute dedicated to Malaria Research (EVIMalaR).

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γδ-T cells promote IFN-γ–dependent Plasmodium pathogenesis upon liver-stage infection

Publication . Ribot, Julie; Neres, Rita; Zuzarte-Luis, Vanessa; Gomes, Anita Q.; Mancio-Silva, Liliana; Mensurado, Sofia; Neves, Daniel; Monteiro Dos Santos, Miguel; Carvalho, Tânia; Landry, Jonathan J. M.; A. Rolo, Eva; Malik, Ankita; Silva, Daniel Varón; Mota, Maria M.; Silva-Santos, Bruno; Pamplona, Ana

Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.

2019Journal article

Restricted access

Host AMPK Is a modulator of Plasmodium liver infection

Publication . Ruivo, Margarida; Vera, Iset; Sales Dias, Joana; Meireles, Patricia; Gural, Nil; Bhatia, Sangeeta N.; Mota, Maria M.; Mancio-Silva, Liliana

Manipulation of the master regulator of energy homeostasis AMP-activated protein kinase (AMPK) activity is a strategy used by many intracellular pathogens for successful replication. Infection by most pathogens leads to an activation of host AMPK activity due to the energetic demands placed on the infected cell. Here, we demonstrate that the opposite is observed in cells infected with rodent malaria parasites. Indeed, AMPK activity upon the infection of hepatic cells is suppressed and dispensable for successful infection. By contrast, an overactive AMPK is deleterious to intracellular growth and replication of different Plasmodium spp., including the human malaria parasite, P. falciparum. The negative impact of host AMPK activity on infection was further confirmed in mice under conditions that activate its function. Overall, this work establishes the role of host AMPK signaling as a suppressive pathway of Plasmodium hepatic infection and as a potential target for host-based antimalarial interventions.

2016Journal article

Open access