title: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; and.
authors.forename: Lisa J
authors.identifier: http://orcid.org/0000-0003-1287-7347
authors.initials: LJ
authors.lastname: Ioannidis
authors.affiliation: Office for Research Ethics and Integrity, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Catherine Q
authors.identifier: http://orcid.org/0000-0002-3577-2700
authors.initials: CQ
authors.lastname: Nie
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; and.
authors.forename: Ann
authors.initials: A
authors.lastname: Ly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; and.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ryg-Cornejo
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; and.
authors.forename: Chris Y
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia; and hansen@wehi.edu.au.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Hansen
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D018512:Parasitemia / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse