Poster Presentation Lorne Infection and Immunity 2014

Diverse cellular sources of CXCL10 modulate different processes involved in the development of severe malaria (#159)

Lisa Ioannidis 1 , Victoria Ryg-Cornejo 2 , Chris Chiu 2 , Catherine Nie 3 , Diana Hansen 2
  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  3. The Burnet Institute, Melbourne, VIC, Australia

Cerebral malaria (CM) is one of the most severe clinical manifestations of Plasmodium falcipaum infection. This syndrome is thought to result from the sequestration of parasitized red blood cells in the brain microvasculature and a strong inflammatory response to infection. Although the role of cytokines in CM has been widely investigated, the role of chemokines remains to be fully elucidated. Case control studies identified the CXCR3 chemokine C-X-C motif chemokine 10 (CXCL10) as a biomarker of CM severity. Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects malaria-infected mice from CM. Malaria-stimulated brain endothelial cells were also shown to produce CXCL10, suggesting that these cells mediate leukocyte recruitment to the site of parasite sequestration. In addition to organ-specific effects, here we found that a lack of CXCL10 during infection reduces parasite biomass, suggesting that this chemokine compromises the induction of protective immunity. To identify the cellular sources of CXCL10 involved in these processes, wild-type and CXCL10-/- mice were irradiated and reconstituted with bone marrow from either wild-type or CXCL10-/- mice. Chimeric mice were infected with luciferase-expressing P. berghei ANKA and parasite biomass was assessed. Chimeras that were unable to express CXCL10 in hematopoietic-derived cells had significantly lower whole body and brain parasite densities than wild-type controls. Conversely, chimeras that could produce CXCL10 in hematopoietic-derived cells had higher whole body biomass and exacerbated brain parasite sequestration compared to knock-out chimeras, indicating that hematopoietic-derived sources of CXCL10 have a detrimental role in controlling parasite growth. Our results suggest that the cells that produce CXCL10 in response to malaria differ in the brain and lymphoid organs and that they control different processes in these two sites: leukocyte recruitment in the brain and parasite biomass in the spleen