Poster Presentation First Malaria World Congress 2018

Resolving clinically overt cerebral malaria by inhibiting accumulation of Ly6Clo pathogenic monocytes in brain microvasculature (#261)

Amy Cohen 1 , Paula Niewold 2 , Caryn van Vreden 3 , Daniel Getts 4 5 , Georges E.R. Grau 1 , Nicholas King 2 3
  1. Vascular Immunology Unit, Department of Pathology, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
  2. Viral Immunopathology, Department of Pathology, University of Sydney, Sydney, NSW, Australia
  3. Advanced Flow Cytometry facility, Centenary Institute, Sydney, NSW, Australia
  4. Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
  5. Cour Pharmaceutical Development Company, Elmhurst, IL, USA

Introduction:

Cerebral malaria (CM) is a fatal complication of Plasmodium infection, partly due to the thrombotic aggregation of inflammatory monocytes in the cerebral blood vessels, although its pathogenesis remains poorly understood. As resistance to existing antimalarial drugs increases worldwide, the need for alternate effective therapeutic strategies is increasingly urgent.

 

Method:

In a preclinical mouse model of CM, we identified Ly6Chi monocyte-derived Ly6Clo monocytes as the main pathological population and successfully targeted these cells with negatively-charged immune-modifying nanoparticles (IMP).  Mice infected with Plasmodium berghei ANKA (PbA) were treated with IMP or artesunate – an effective anti-malarial drug – alone or in combination, at the onset of the neurological syndrome. Brain, lungs, and spleen were analysed by flow cytometry and fluorescence microscopy.

 

Results:

IMP treatment alone prevented CM in 50% of Plasmodium berghei ANKA-infected mice in early treatment from D3 post infection. Strikingly, 88% of PbA-infected mice survived following combined IMP and artesunate treatment at the onset of the neurological syndrome, while all mock-treated animals succumbed to CM, as expected. In comparison, treatment with artesunate or IMP alone resulted in 56% or 10% protection, respectively. Combination treatment effectively addressed three major pathological hallmarks, namely parasitaemia, circulating microvesicle numbers and the accumulation of Ly6Clo monocytes in the brain microvasculature, as well as resulting in robust immunity to re-infection.

 

Conclusion:

The success of IMP and artesunate treatment combined at a late stage of infection suggests a viable alternative for current CM treatments.