Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease

Abstract

CXCL10, or IFN-γ–inducible protein 10, is a biomarker associated with increased risk for Plasmodium falciparum–mediated cerebral malaria (CM). Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM. In addition to organ-specific effects, the absence of CXCL10 during infection was also found to reduce parasite biomass. To identify the cellular sources of CXCL10 responsible for these processes, we irradiated and reconstituted wild-type (WT) and CXCL10−/− mice with bone marrow from either WT or CXCL10−/− mice. Similar to CXCL10−/− mice, chimeras unable to express CXCL10 in hematopoietic-derived cells controlled infection more efficiently than WT controls. In contrast, expression of CXCL10 in knockout mice reconstituted with WT bone marrow resulted in high parasite biomass levels, higher brain parasite and leukocyte sequestration rates, and increased susceptibility to CM. Neutrophils and inflammatory monocytes were identified as the main cellular sources of CXCL10 responsible for the induction of these processes. The improved control of parasitemia observed in the absence of CXCL10-mediated trafficking was associated with a preferential accumulation of CXCR3+CD4+ T follicular helper cells in the spleen and enhanced Ab responses to infection. These results are consistent with the notion that some inflammatory responses elicited in response to malaria infection contribute to the development of high parasite densities involved in the induction of severe disease in target organs.

Neutrophil-derived chemokines on the road to immunity

“…Similar results were also observed in a model of compensatory anti-inflammatory response syndrome [75]. Finally, in mice infected with Plasmodium berghei ANKA, neutrophil-and monocyte-derived CXCL10 have been shown to induce the migration of anti-Plasmodium effector cells out of lymphoid secondary organs [76], therefore causing an impaired control of the blood stage of malaria and the consequent entrapment of parasitized red blood cells into the cerebral-microcirculation [76].…”

Th1-like Plasmodium -Specific Memory CD4 + T Cells Support Humoral Immunity

“…The acquisition of Th1-associated CXCR3, T-bet, and IFN-γ expression by pre-Tfh cells is reported to constrain their migration and development into competent B helper cells in follicles (Ioannidis et al, 2016, Ryg-Cornejo et al, 2016). We and others have shown that excessive IFN-γ limits humoral immunity (Zander et al, 2015, Ryg-Cornejo et al, 2016).…”

Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of γδ T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea

“…P. berghei -infected mice were treated at day 5 post-infection to avoid progression to cerebral malaria. Drug treatment consisted of an intraperitoneal injection of CQ (10 mg/kg) and pyrimethamine (10 mg/kg) followed by CQ- and pyrimethamine-containing water for 5 days as described previously [52]. Livers and spleens were removed at different time points following completion of drug treatment.…”