A primate model of severe malarial anaemia: a comparative pathogenesis study

摘要

Severe malarial anaemia (SMA) is the most common life-threatening complication of Plasmodiumfalciparum infection in African children. SMA is characterised by haemolysis and inadequateerythropoiesis, and is associated with dysregulated infammatory responses and reduced complementregulatory protein levels (including CD35). However, a deeper mechanistic understanding of thepathogenesis requires improved animal models. In this comparative study of two closely relatedmacaque species, we interrogated potential causal factors for their diferential and temporalrelationships to onset of SMA. We found that rhesus macaques inoculated with blood-stage Plasmodiumcoatneyi developed SMA within 2 weeks, with no other severe outcomes, whereas infected cynomolgusmacaques experienced only mild/ moderate anaemia. The abrupt drop in haematocrit in rhesus wasaccompanied by consumption of haptoglobin (haemolysis) and poor reticulocyte production. Rhesusdeveloped a greater infammatory response than cynomolgus macaques, and had lower baseline levelsof CD35 on red blood cells (RBCs) leading to a signifcant reduction in the proportion of CD35+ RBCsduring infection. Overall, severe anaemia in rhesus macaques infected with P. coatneyi has similarfeatures to SMA in children. Our comparisons are consistent with an association of low baseline CD35levels on RBCs and of early infammatory responses with the pathogenesis of SMA.