Oral Presentation The Australasian Society for Immunology 2017 Annual Scientific Meeting

Resolving cerebral malaria by inhibiting accumulation of pathogenic monocytes in the brain microvasculature (#72)

Paula Niewold 1 , Amy Cohen 1 , Caryn van Vreden 1 , Daniel R Getts 2 , Georges Grau 1 , Nicholas J King 1
  1. University of Sydney, Sydney, NSW, Australia
  2. Northwestern University, Evanston, USA

Severe malaria is caused by the mosquito-borne parasite Plasmodium falciparum and is associated with several lethal complications including metabolic abnormalities, acute respiratory distress syndrome and cerebral malaria (CM). The most recent WHO reports indicate there were 212 million cases of malaria worldwide in 2015, with an estimated 429,000 deaths annually. CM is associated with cerebral blood vessel occlusion by collections of adherent, parasitised red blood cells, platelets, inflammatory monocytes and T cells. Current anti-parasitic treatments for CM have low efficacy in advanced infection, as occlusion of the brain microvasculature by accumulating blood cells leads to neurological damage. Therefore, we sought to identify cells that contributed to pathology as novel targets for immune-modulatory therapies.

We used a preclinical mouse model of CM, reproducing over 25 pathophysiological and immunological features of human disease, to study leukocyte accumulation in the cerebral vasculature using high-dimensional flow cytometry and computational analysis. In combination with adoptive transfer experiments, our study revealed that Ly6Clo monocytes, one of the main pathogenic subsets in the brain vasculature, were derived from circulating inflammatory Ly6Chi monocytes. Previous studies have shown that immune modifying particles (IMP) can be used to target Ly6Chi monocytes, preventing their migration to inflammatory foci. As such, we treated mice with 2 doses of IMP upon appearance of neurological signs of CM, in combination with the WHO-recommended anti-parasitic artesunate. This combination therapy resulted in 88% survival in animals that would otherwise have succumbed to disease within 36 hours, and was associated with reduction of cellular accumulation in the brain vasculature and lung, clearance of parasitaemia and immunity to reinfection without additional treatment.

In conclusion, through a detailed study of the immune response in CM, directed targeting of pathogenic immune subsets lead to a highly successful combination therapy, resulting in nearly 90% survival in an otherwise lethal syndrome.