Abstract
Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1-/- mice and wild type mice suffering from ECM. Importantly, CD8+ T cells were increased in the spleens of ECM-protected Ifnar1-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+ T cell infiltration into the brain and increased ECM induction in PbAAma1OVA-infected Ifnar1-/- mice. However, eosinophil-depletion did not reduce the CD8+ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+ T cell migration and proliferation during PbAAma1OVA-infection in Ifnar1-/- mice and thereby are contributing to the protection from ECM.
Highlights
Despite major elimination efforts, malaria is still one of the ten leading causes of death in developing countries, with over 400,000 annual deaths [1]
experimental cerebral malaria (ECM) is the result of strong inflammatory immune responses towards PbA parasites in susceptible C57BL/6 mice driven by CD8+ T cells and interferon gamma (IFN-g) [13, 34, 44]
Since type I IFNs are relevant in T cell activation, we investigated whether this protection was due to an impaired antigen-specific cytotoxic activity
Summary
Malaria is still one of the ten leading causes of death in developing countries, with over 400,000 annual deaths [1]. Plasmodium falciparum is responsible for over 99% of malaria cases in Africa and can lead to serious complications such as cerebral malaria (CM) [1]. This complication is mainly caused by inflammatory immune responses of the infected host to parasite-specific components and toxins [2, 3]. Several experimental models are used to investigate the immune responses towards parasites such as infection of C57BL/6 mice with Plasmodium berghei ANKA. The immune system has to maintain the balance of generating adequate immune responses against the parasite and preventing selfinflicted damage [16, 21]
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