Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood‐stage Plasmodium bergheiANKA

Abstract

Cerebral malaria is a severe complication ofEur. J. Immunol. 2013Immunol. . 43: 2683Immunol. -2695 Plasmodium falciparum-infected children and young adults [1]. Cerebral malaria pathophysiology is still poorly understood, combining cerebral vascular obstruction, and exacerbated immune responses. Indeed, investigations in humans and mice documented the sequestration of erythrocytes, parasitized or not, platelets and leucocytes in cerebral blood vessels with an increased proinflammatory cytokine expression [1][2][3]. The specific role of T cells in cerebral malaria pathogenesis has been difficult to address in humans. In mice however, T-cell sequestration and activation in the brain are crucial steps for experimental cerebral malaria (ECM) development after Plasmodium berghei ANKA (PbA) infection [4][5][6][7]. In particular, αβ-CD8 + T cells sequestrated in the brain play a pathogenic, effector role for ECM development [6], and we showed recently a role for protein kinase C-θ (PKC-θ) in PbAinduced ECM pathogenesis [8]. Besides being a critical regulator of TCR signaling and T-cell activation, PKC-θ is involved in interferon type I/II signaling in human T cells [9]. Type II IFN-γ is essential for PbA-induced ECM development [10][11][12], promoting CD8 + T-cell accumulation in the brain [7,[12][13][14]. Type IIFNs are induced during viral infection but they also contribute to the antibacterial immune response. ResultsThe IFN-γ pathway is essential for ECM development upon sporozoite PbA infectionThe IFN-γ pathway is central for ECM development after bloodstage PbA infection. We first assessed the role of this pathway in preerythrocytic/intrahepatic stage infection by investigating ECM neurological signs development in IFN-γR1 −/− mice. Following the injection of 1000 sporozoites, 60% of the WT control mice developed typical ECM neurological symptoms, such as ataxia, loss of grip strength, progressive paralysis, and coma, and succumbed within 8-9 days, as previously described [22]. In contrast, IFN-γR1 −/− mice were fully resistant to the same challenge, surviving 30 days with no ECM neurological signs (Fig. 1A). Therefore, type II IFN-γ pathway is essential for ECM development after PbA sporozoite infection.Hampered ECM development in the absence of IFN-α/β pathway upon hepatic or blood-stage PbA infectionThe role of type I IFN-α/β versus type II IFN-γ pathways in ECM development after infection with hepatic or blood-stage PbA was then assessed in mice deficient for either IFNAR1 or IFN-γR1. IFNAR1 −/− mice were partially protected against ECM following sporozoite-initiated infection, only 20% dying before day 10, and 40% eventually developing typical ECM neurological symptoms, which reflected a delayed ECM development after infection with sporozoites ( Fig. 1A), as compared with WT control mice, 60% of which developed ECM and died before day 10, and IFN-γR1-deficient mice, which were fully resistant to PbA challenge. After injection of PbA-parasited red blood cells (10 5 pRBC/ mouse), WT mice succumbed within 7-...

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

“…In murine models of Plasmodium in which death is associated with immunopathology, such as P. berghei, the absence of IFNAR leads to reduced tissue pathology and reduced mortality (24,(67)(68)(69). Treatment with IFN-α or IFN-β, both prior to and during infection, however, reduces lethality, implying a role for early parasite control in contributing to lethality (70,71).…”

“…To examine antigen-specific CD4 + T cells responding to infection, P. yoelii were generated that constitutively express the Lymphocytic choriomeningitis virus-derived (LCMV-derived) glycoprotein (GP) epitope (GP [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] ). This allows for the identification and analysis of antigen-specific CD4 + T cells using previously described GP66:I-A B tetramer enrichment strategies (16).…”

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

“…, or tbk Δ/Δ mice survived (or lived) longer than the WT in lethal PbANKA infection (22,46,47). Variations at IFN-α promoter (17470-G/G and L168V-G/G genotypes) or receptor IFNAR1 were associated with protection against severe malaria (43,46), whereas variation at IFNA2-173 and IFNA8-884 reduced IFN-α production and increased susceptibility to severe malarial anemia and mortality (44).…”

“…, or tbk Δ/Δ mice infected with P. berghei (compared with lethal infection in wt mice) suggest that IFN-I may also contribute to malaria pathology in late stages of infection (22,46,47). The relationship of IFN-I response dynamics and protection or pathology in malaria infection requires further investigation.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Type I IFNs were shown to mediate protection against blood-stage (164) and liver-stage (163,165) malaria in infected animals. However, recent studies revealed that type I IFNs increase host susceptibility to cerebral malaria (162,166).…”