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

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

doi:10.1038/s42003-018-0216-2

Paula Niewold, Daniel R Getts + Show 4 more

Open Access

https://doi.org/10.1038/s42003-018-0216-2

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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 Ly6Clo monocytes as a major component of the immune infiltrate in both organs in a preclinical mouse model. Specifically targeting Ly6Clo 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.

Highlights

Current treatment of severe malaria and associated cerebral malaria (CM) and respiratory distress syndromes are directed primarily at the parasite
Intravascular sequestration of monocytes has been identified in both human CM2,3,11 and mouse experimental CM (ECM)[12] and these cells are a major source of pro-inflammatory cytokines and chemokines in CM pathogenesis
Ly6Clo and CX3CR1hi expression is observed on microglia, this pattern is found on Ly6Clo monocytes, and CX3CR1 expression on the latter is associated with ligand-mediated arrest on activated vascular endothelium[26,27]

Summary

Introduction

Current treatment of severe malaria and associated cerebral malaria (CM) and respiratory distress syndromes are directed primarily at the parasite. Targeting Ly6Clo 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. 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. Similar vascular involvement in the lungs results in blood vessel leakage and interstitial leucocyte accumulation, leading to malaria-associated RD and acute respiratory decompensation[5]. Both syndromes are in most cases lethal without treatment. Abrogation of encephalitis was achieved when IMP were administered after development of clinical signs[16]

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