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.

Granzyme B Expression by CD8+ T Cells Is Required for the Development of Experimental Cerebral Malaria

“…2B). However, by using a transgenic PbA-luc strain, we were able to measure live parasite biomass in mice, which takes into account not only pRBCs in circulating blood, but also those accumulating in tissue microvasculature, as we have previously described (40,43). By measuring parasite-derived bioluminescence emanating from PbA-luc-infected wild-type and gzmB 2/2 mice, we observed significantly lower total parasite burden in gzmB 2/2 mice (Fig.…”

“…Therefore, it appears that extrinsic factors may act upon primed CD4 + T cells to cause them to be pathogenic in one situation (wild-type mice), and antiparasitic in another (gzmB 2/2 mice). One possibility is that retention of T cells in the spleen facilitates antiparasitic activity, whereas migration out of the spleen conditions peripheral tissues to sequester parasites, an idea also proposed by others (43). The exact mechanisms by which CD4 + T cells and CD8 + T cells promote parasite tissue accumulation in the brain is currently unknown, but may be linked to their local production of inflammatory cytokines, such as IFN-g, lymphotoxin a, and TNF, which increase expression of endothelial adhesion molecules that can potentially mediate binding of leukocytes, pRBCs, or both (49,50).…”

Genetic susceptibility to systemic lupus erythematosus protects against cerebral malaria in mice

“…In mice, cerebral malaria is characterized by a complex cascade of events including breakdown of the bloodbrain barrier, sequestration of iRBCs in the brain microvessels, accumulation of leukocytes in the brain, and the production of proinflammatory cytokines (25,26). The analyses of a variety of mice deficient in cytokines (27,28), chemokines and chemokine receptors (29)(30)(31), and TLRs (32) have implicated a variety of immune mechanisms in resistance to cerebral malaria but have not led to a clear picture of the underlying cause of disease pathology. Although the genetic alterations in the SLE-prone mice described here are well defined, the cellular and molecular mechanism by which these alterations result in autoimmunity is not fully understood.…”

Hyposplenism: Comparison of different methods for determining splenic function

“…Spleen function consists of several aspects, according to the three anatomical splenic subunits: (1) the white pulp, containing B-cell follicles, (2) the marginal zone, containing specialized macrophages and memory B-cells, and (3) the red pulp, where erythrocytes are filtered from the circulation by entrapment in the splenic cords and subsequent phagocytosis, as well as by retention through receptor-ligand interaction [18]. These different splenic functions are associated with different methods to determine the level of dysfunction of the organ [2].…”