Abstract
Malaria is a global disease associated with considerable mortality and morbidity. An appropriately balanced immune response is crucial in determining the outcome of malarial infection. The glucocorticoid (GC) metabolising enzyme, 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) converts intrinsically inert GCs into active GCs. 11β-HSD1 shapes endogenous GC action and is immunomodulatory. We investigated the role of 11β-HSD1 in two mouse models of malaria. 11β-HSD1 deficiency did not affect survival after malaria infection, but it increased disease severity and parasitemia in mice infected with Plasmodium chabaudi AS. In contrast, 11β-HSD1 deficiency rather decreased parasitemia in mice infected with the reticulocyte-restricted parasite Plasmodium berghei NK65 1556Cl1. Malaria-induced antibody production and pathology were unaltered by 11β-HSD1 deficiency though plasma levels of IL-4, IL-6 and TNF-α were slightly affected by 11β-HSD1 deficiency, dependent on the infecting parasite. These data suggest that 11β-HSD1 is not crucial for survival of experimental malaria, but alters its progression in a parasite strain-specific manner.
Highlights
Malaria is a global health problem with an estimated 200 million clinical cases and 438,000 deaths in 20151
To determine whether peripheral reactivation of endogenous GCs has an effect on malarial disease, Hsd11b1Del/Del and WT mice were infected with the malarial parasite P. chabaudi AS (PcAS)
To determine whether peripheral reactivation of endogenous GCs has an effect on malarial disease, we studied the phenotype of Hsd11b1Del/Del mice. 11β-HSD1 deficiency altered parasitemia and clinical disease score in mice infected with PcAS or Plasmodium berghei NK65 (PbNK65) 1556Cl1
Summary
Malaria is a global health problem with an estimated 200 million clinical cases and 438,000 deaths in 20151. 11β-HSD1-deficient mice are more susceptible to sublethal dose LPS endotoxemia as shown by an elevated weight loss and increased circulatory levels of pro-inflammatory tumor necrosis factor-α (TNF-α), IL-6, and IL-12p40. This was attributed to a macrophage hypersensitive state with increased signalling of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK)[32]. PcAS-infected C57Bl/6 mice are able to clear the parasite and survive the infection despite a transient phase of liver inflammation[36] This model is frequently used to study immune mechanisms since a parasite-controlling immune response develops.
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