Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria

Amante, Fiona H., Haque, Ashraful, Stanley, Amanda C., de Labastida Rivera, Fabian, Randall, Louise M., Wilson, Yana A., Yeo , Gladys, Pieper, Christian, Crabb, Brendan S., de Koning-Ward, Tania F., Lundie, Rachel J., Good, Michael F., Pinzon-Charry, Alberto, Pearson, Mark S., Duke, Mary G., McManus, Donald P., Loukas, Alex, Hill, Geoff R., and Engwerda, Christian R. (2010) Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. Journal of Immunology, 185 (6). pp. 3632-3642.

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Abstract

Cerebral malaria is a severe complication of malaria. Sequestration of parasitized RBCs in brain microvasculature is associated with disease pathogenesis, but our understanding of this process is incomplete. In this study, we examined parasite tissue sequestration in an experimental model of cerebral malaria (ECM). We show that a rapid increase in parasite biomass is strongly associated with the induction of ECM, mediated by IFN-γ and lymphotoxin α, whereas TNF and IL-10 limit this process. Crucially, we discovered that host CD4⁺ and CD8⁺ T cells promote parasite accumulation in vital organs, including the brain. Modulation of CD4⁺ T cell responses by helminth coinfection amplified CD4⁺ T cell-mediated parasite sequestration, whereas vaccination could generate CD4⁺ T cells that reduced parasite biomass and prevented ECM. These findings provide novel insights into immune-mediated mechanisms of ECM pathogenesis and highlight the potential of T cells to both prevent and promote infectious diseases.

Item ID: 28573
Item Type: Article (Research - C1)
ISSN: 1550-6606
Keywords: gamma interferon; interleukin 10; lymphotoxin alpha beta; tumor necrosis factor; adoptive transfer; animal experiment; animal model; animal tissue; article; blood level; brain; brain malaria; CD4+ T lymphocyte; CD8+ T lymphocyte; confocal microscopy; controlled study; female; helminth; immunization; immunofluorescence; immunomodulation; lung; microbial biomass; mixed infection; mouse; nonhuman; parasite tissue sequestration; pathogenesis; priority journal; transgenic organism; animals; brain; CD4-positive T-lymphocytes; disease models, animal; erythrocytes; female; gastrointestinal tract; kidney; liver; lung; malaria, cerebral; mice; inbred C57BL; knockout; mutant strains; transgenic; organ specificity; Plasmodium berghei; severity of illness index; spleen
Funders: National Health and Medical Research Council (NHMRC)
Date Deposited: 19 Aug 2013 05:52
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110803 Medical Parasitology @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 100%
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