Experimental severe malaria is resolved by targeting newly-identified monocyte subsets using immune-modifying particles combined with artesunate

Paula Niewold; Amy Cohen; Caryn van Vreden; Daniel R Getts; Georges E Grau; Nicholas J C King

doi:10.1038/s42003-018-0216-2

Experimental severe malaria is resolved by targeting newly-identified monocyte subsets using immune-modifying particles combined with artesunate

Commun Biol. 2018 Dec 13:1:227. doi: 10.1038/s42003-018-0216-2. eCollection 2018.

Authors

Paula Niewold^#¹, Amy Cohen^#², Caryn van Vreden³, Daniel R Getts^{4

5}, Georges E Grau^#², Nicholas J C King^#^{1

3}

Affiliations

¹ 1Viral Immunopathology, Discipline of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050 Australia.
² 2Vascular Immunology Unit, Discipline of Pathology and Bosch Institute, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050 Australia.
³ 3Sydney Cytometry, The University of Sydney and The Centenary Institute, Camperdown, NSW 2050 Australia.
⁴ 4Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 USA.
⁵ TcR2, Therapeutics, 100 Binney Street, Suite 710, Cambridge, MA 02142 USA.

^# Contributed equally.

Abstract

Current treatment of severe malaria and associated cerebral malaria (CM) and respiratory distress syndromes are directed primarily at the parasite. Targeting the parasite has only partial efficacy in advanced infection, as neurological damage and respiratory distress are due to accumulation of host blood cells in the brain microvasculature and lung interstitium. Here, computational analysis identifies Ly6C^lo monocytes as a major component of the immune infiltrate in both organs in a preclinical mouse model. Specifically targeting Ly6C^lo monocyte precursors, identified by adoptive transfer, with immune-modifying particles (IMP) prevents experimental CM (ECM) in 50% of Plasmodium berghei ANKA-infected mice in early treatment protocols. Furthermore, treatment at onset of clinical ECM with 2 doses of a novel combination of IMP and anti-malarial drug artesunate results in 88% survival. This combination confers protection against ECM and mortality in late stage severe experimental malaria and provides a viable advance on current treatment regimens.