Artikel
Doxycycline inhibits experimental cerebral malaria by altering T cell responses and reducing inflammatory mediators
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Veröffentlicht: | 17. Dezember 2014 |
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Gliederung
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We investigated the impact of doxycycline treatment on Plasmodium berghei ANKA (PbA) induced experimental cerebral malaria (ECM). The complex inflammatory networks triggered by the parasite leads to the destruction of the blood brain barrier (BBB). Administration of doxycycline prevented neuropathology in PbA infected mice. Local inflammation was reduced to a minimum and BBB damage was prevented.
These effects were still detected when mice were infected with a higher parasite load, equalizing peripheral parasitemia in untreated (normal infection) and treated (high dose infection) mice on day 6 post infection. Other tetracycline derivatives show similar effects, but only those with known immune-regulatory properties.
Our results provide evidence that the inhibition of ECM is to a large extend by anti-inflammatory actions of doxycycline, despite observed anti-parasitic effects.
Analyzing brain tissue by FACS and ELISA, we found that in treated animals, immune cell infiltration was impaired and the generation of inflammatory cytokines like CCL5 and TNF was reduced compared to infected controls. Especially T cells found to be reduced in number and activation. The T cells accumulated in the spleen and despite similar general activation compared to PbA infected controls, these cells showed reduced parasite-specific cytotoxicity after doxycycline treatment, as shown by Granzyme B production and an in vivo kill.
Our results suggest that during ECM in addition to known anti-parasitic effects several systemic and local inflammatory processes are targeted by doxycycline, inhibiting BBB disruption and neuropathology. Thus we provide theoretical support for retaining doxycycline in the treatment of severe human malaria.
Note: The authors Janina M. Küpper and Kim E. Schmidt contributed equally. Sabine Specht and Achim Hoerauf shared the senior authorship.