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. About 2.5 million people die of severe Plasmodium falciparum malaria every year. Experimental evidence from human studies and animal models indicates that severe disease syndromes arise in many organs through the sequestration of parasitized erythrocytes in vascular beds and the resulting recruitment of inflammatory leukocytes. Thus in this infection, cell-mediated immune responses appear to play a dual role by mediating protection against the parasite and also contributing to pathogenesis. Using a rodent model of cerebral malaria, we have previously found that during infection, inflammatory leukocytes are recruited to the brain via the CXCR3 trafficking pathway. Here we investigated whether blockade of the CXCR3 ligand, IP-10, alleviates brain intravascular inflammation and has an impact on the development of parasite-specific cellular immune responses involved in the control of parasitemia. We found that mice lacking IP-10 or receiving anti-IP-10 neutralizing antibodies had reduced cerebral intravascular inflammation and were protected against fatality. Inhibition of IP-10-mediated trafficking also resulted in retention of parasite-specific T cells in the spleen, facilitating control of parasite burden. Thus, IP-10-dependent trafficking critically controls the balance between pathogenic organ-specific inflammation and spleen-mediated protective immunity to malaria.