Recombinant Human IFN-α Inhibits Cerebral Malaria and Reduces Parasite Burden in Mice

Abstract

Most C57BL/6 mice infected i.p. with Plasmodium berghei ANKA (PbA) die between 7 and 14 days with neurologic signs, and the remainder die later (>15 days) with severe anemia. Daily i.p. injections of a recombinant human IFN-α (active on mouse cells) prevented death by cerebral malaria (87% deaths in the control mice vs 6% in IFN-α-treated mice). The mechanisms of this IFN-α protective effect were multiple. IFN-α-treated, PbA-infected mice showed 1) a marked decrease in the number of PbA parasites in the blood mediated by IFN-γ, 2) less sequestered parasites in cerebral vessels, 3) reduced up-regulation of ICAM-1 expression in brain endothelial cells, 4) milder rise of blood levels of TNF, 5) increased levels of IFN-γ in the blood resulting from an increased production by splenic CD8+ T cells, and 6) fewer leukocytes (especially CD8+ T cells) sequestered in cerebral vessels. On the other hand, IFN-α treatment did not affect the marked anemia observed in PbA-infected mice. Survival time in IFN-α-treated mice was further increased by performing three blood transfusions over consecutive days.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…In an earlier study, injection of interferon-inducing agents, such as Newcastle disease virus, protected against lethal Plasmodium infection [42]. Similarly, administration of a mutant form of human IFN-a, engineered for reactivity in mice, protected against experimental cerebral malaria [43]. However, the importance of endogenous IFN-I responses during bloodstage Plasmodium infection is difficult to ascertain from these studies.…”

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). In nonlethal murine models, the role of IFNAR signals vary depending on the strain of parasite and experimental conditions.…”

“…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).…”

Statins Fail to Improve Outcome in Experimental Cerebral Malaria and Potentiate Toll-Like Receptor-Mediated Cytokine Production by Murine Macrophages

“…A recent study showed that treatment of P. berghei -infected C57BL/6 mice with recombinant human IFN-γ significantly improved survival, which suggested a protective role for this cytokine during experimental cerebral malaria. 30 Therefore, the decrease in IFN-γ observed in simvastatin-treated mice could potentially contribute to adverse clinical outcomes in experimental cerebral malaria. Further more, IL-6 levels were greater in statin-treated mice on day 6 ( Figure 2B ).…”