title: IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection.
abstract: Plasmodium falciparum malaria causes 660 million clinical cases with over 2 million deaths each year. Acquired host immunity limits the clinical impact of malaria infection and provides protection against parasite replication. Experimental evidence indicates that cell-mediated immune responses also result in detrimental inflammation and contribute to severe disease induction. In both humans and mice, the spleen is a crucial organ involved in blood stage malaria clearance, while organ-specific disease appears to be associated with sequestration of parasitized erythrocytes in vascular beds and subsequent recruitment of inflammatory leukocytes. Using a rodent model of cerebral malaria, we have previously found that the majority of T lymphocytes in intravascular infiltrates of cerebral malaria-affected mice express the chemokine receptor CXCR3. Here we investigated the effect of IP-10 blockade in the development of experimental cerebral malaria and the induction of splenic anti-parasite immunity. We found that specific neutralization of IP-10 over the course of infection and genetic deletion of this chemokine in knockout mice reduces cerebral intravascular inflammation and is sufficient to protect P. berghei ANKA-infected mice from fatality. Furthermore, our results demonstrate that lack of IP-10 during infection significantly reduces peripheral parasitemia. The increased resistance to infection observed in the absence of IP-10-mediated cell trafficking was associated with retention and subsequent expansion of parasite-specific T cells in spleens of infected animals, which appears to be advantageous for the control of parasite burden. Thus, our results demonstrate that modulating homing of cellular immune responses to malaria is critical for reaching a balance between protective immunity and immunopathogenesis.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Catherine Q
authors.initials: CQ
authors.lastname: Nie
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bernard
authors.forename: M Ursula
authors.initials: MU
authors.lastname: Norman
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Lundie
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
authors.forename: Diana S
authors.initials: DS
authors.lastname: Hansen