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Abstract
Malaria is a causative factor in about 500.000 deaths each year world-wide. Cerebral malaria is a particularly severe complication of this disease and thus associated with an exceedingly high mortality. Malaria retinopathy is an ocular manifestation often associated with cerebral malaria, and presumably shares a substantial part of its pathophysiology. Here, we describe that indeed murine malaria retinopathy reproduced the main hallmarks of the corresponding human disease. In the living animal, we were able to follow the circulation and cellular localization of malaria parasites transgenically labelled with GFP via non-invasive in vivo retinal imaging. We found that malaria parasites cross the blood-retinal-barrier and infiltrate the neuroretina, concomitant with an extensive, irreversible, and long-lasting retinal neurodegeneration. Furthermore, anti-malarial treatment with dihydroartemisinin strongly diminished the load of circulating parasites but resolved the symptoms of the retinopathy only in part. In summary, we introduce here a novel preclinical model for human cerebral malaria that is much more directly accessible for studies into disease pathophysiology and development of novel treatment approaches. In vivo retinal imaging may furthermore serve as a valuable tool for the early diagnosis of the human disease.
Highlights
Malaria is a causative factor in about 500.000 deaths each year world-wide
The C57BL/6J mouse strain is vulnerable to developing the symptoms of cerebral malaria, something that typically occurs within 8–10 days post-infection (DPI) and is usually fatal after 1–2 more days[11]
After 6DPI animals were treated with dihydroartemisinin (DHA), a standard anti-malarial drug and closely monitored for further 12 days until the end of the experiment (18DPI) and full histological work-up and analysis (Fig. 1)
Summary
Malaria is a causative factor in about 500.000 deaths each year world-wide. Cerebral malaria is a severe complication of this disease and associated with an exceedingly high mortality. We describe that murine malaria retinopathy reproduced the main hallmarks of the corresponding human disease. We introduce here a novel preclinical model for human cerebral malaria that is much more directly accessible for studies into disease pathophysiology and development of novel treatment approaches. The C57BL/6J mouse strain is vulnerable to developing the symptoms of cerebral malaria, something that typically occurs within 8–10 days post-infection (DPI) and is usually fatal after 1–2 more days[11]. Even though the mouse is an often used model system for studies into the underlying pathophysiology as well as for drug candidate testing and treatment development[12], malaria-induced murine retinopathy has not been studied in any detail[13]. Our results demonstrate that the ocular and retinal symptoms in the mouse model are reproducing the main hallmarks of human malaria retinopathy. We provide strong in vivo and ex vivo evidence that malaria parasites cross www.nature.com/scientificreports/
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