Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria.
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-gamma and lymphotoxin alpha, 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.
Amante
Fiona H
FH
Australian Centre for Vaccine Development, Brisbane, Queensland, Australia.
Haque
Ashraful
A
Stanley
Amanda C
AC
Rivera
Fabian de Labastida
Fde L
Randall
Louise M
LM
Wilson
Yana A
YA
Yeo
Gladys
G
Pieper
Christian
C
Crabb
Brendan S
BS
de Koning-Ward
Tania F
TF
Lundie
Rachel J
RJ
Good
Michael F
MF
Pinzon-Charry
Alberto
A
Pearson
Mark S
MS
Duke
Mary G
MG
McManus
Donald P
DP
Loukas
Alex
A
Hill
Geoff R
GR
Engwerda
Christian R
CR
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000469:parasitology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D005260:Female; D041981:Gastrointestinal Tract / Q000098:blood supply / Q000276:immunology / Q000469:parasitology; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000469:parasitology; D008099:Liver / Q000098:blood supply / Q000276:immunology / Q000469:parasitology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000469:parasitology; D016779:Malaria, Cerebral / Q000097:blood / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000276:immunology; D010962:Plasmodium berghei / Q000254:growth & development / Q000276:immunology*; D012720:Severity of Illness Index; D013154:Spleen / Q000098:blood supply / Q000276:immunology / Q000469:parasitology