Severe malaria, particularly cerebral malaria, has been our major research interest since over 3 decades. In addition to sequestration of infected erythrocytes in deep microvessels, cerebral malaria is characterised by a massive immunopathological reaction, which we have tried to understand better, using experimental models in mice, in vitro co-culture models using human brain endothelium and clinical studies (reviewed in Trends Immunol 24:491, 2003 and Nat Rev Immunol 9:722, 2005).
Evidence has emerged that an important part of immunopathological reactions is the release of extracellular vesicles, notably microvesicles (nano-size fragments of plasma membranes, formerly called microparticles), whose production is enhanced by TNF (J Clin Invest 104: 93, 1999) and which are found in high levels in the plasma of patients with cerebral malaria (JAMA 291:2542, 2004). An effector role for microvesicles in immunopathogenesis is supported by the following evidence: 1./ microvesicles can alter endothelial cell phenotype and function (FASEB J 10:3449, 2009), 2./ microvesicles are strong pro-inflammatory elements (PLoS Pathog 6:e1000744, 2010), 3./ blocking microvesicle production is beneficial for endothelial integrity (PLoS Med 2:e245, 2005, Int J Innov Med Health Sci 7:1, 2016) and can prevent mortality due to experimental cerebral malaria (PNAS 105:1321, 2008), and 4./ interfering with microvesicle binding to target cells reduces their activation (PLoS ONE 5:e11869, 2010).
More recently, in the murine model, we have identified a novel subset of pathogenic monocytes and demonstrated that immune-modulatory particles (IMP) can dramatically protect against cerebral and pulmonary lesions, with evidence of a down-modulation of immunopathology, including plasma microvesicle levels. Moreover, we showed that a combination of established antimalarials and IMP was highly effective (88% survival, even when given after neurological signs were present). The late stage success of this combination therapy in mice highlights the novel potential of immunomodulatory treatments in severe malaria and suggests a potential avenue for human translation.