The role of chemokines in severe malaria: more than meets the eye

Abstract

SUMMARYPlasmodium falciparum malaria is responsible for over 250 million clinical cases every year worldwide. Severe malaria cases might present with a range of disease syndromes including acute respiratory distress, metabolic acidosis, hypoglycaemia, renal failure, anaemia, pulmonary oedema, cerebral malaria (CM) and placental malaria (PM) in pregnant women. Two main determinants of severe malaria have been identified: sequestration of parasitized red blood cells and strong pro-inflammatory responses. Increasing evidence from human studies and malaria infection animal models revealed the presence of host leucocytes at the site of parasite sequestration in brain blood vessels as well as placental tissue in complicated malaria cases. These observations suggested that apart from secreting cytokines, leucocytes might also contribute to disease by migrating to the site of parasite sequestration thereby exacerbating organ-specific inflammation. This evidence attracted substantial interest in identifying trafficking pathways by which inflammatory leucocytes are recruited to target organs during severe malaria syndromes. Chemo-attractant cytokines or chemokines are the key regulators of leucocyte trafficking and their potential contribution to disease has recently received considerable attention. This review summarizes the main findings to date, investigating the role of chemokines in severe malaria and the implication of these responses for the induction of pathogenesis and immunity to infection.

Inhibition of placental mTOR signaling provides a link between placental malaria and reduced birthweight

“…This model proposes that the placenta regulates its nutrient transport function to match maternal supply and fetal demand by responding to upstream maternal signals and modulating placental function, including transplacental amino acid transport [23, 24]. In placental malaria-associated intervillositis, maternal mononuclear cells activated by infected erythrocytes in the intervillous space release inflammatory mediators that create a distinct milieu characterized by elevated levels of cytokines and chemokines such as IFN-γ, TNF, IL-10, MCP-1, MIP-1α, IL-8, CCL2, and CCL3 [25–27]. Some of these circulating inflammatory mediators could be responsible for the inhibition of placental mTOR signaling we observed in the placentas of women with placental malaria with intervillositis.…”

Pathogenesis of cerebral malaria—inflammation and cytoadherence

“…Other cytokines have been implicated too (Hunt and Grau, 2003; Boeuf et al, 2012; Ioannidis et al, 2014), but the results of these studies are hard to interpret as it depends on which control group it is compared to; NCM, severe malarial anemia, other encephalitis, other febrile illnesses or even healthy individuals. In addition, patients often have other infections, especially African children, so the cytokine profile may not be a full reflection of the Plasmodium component of infection.…”

From within host dynamics to the epidemiology of infectious disease: Scientific overview and challenges

“…, see [20; 36; 74; 81; 82; 83; 84; 85; 86; 87; 88]). Because the parasite is threatened by the immune system, it has evolved escape strategies, including the intriguing use of antigenic variation mechanisms [89; 90; 91].…”