Abstract
Although the role of systemic proinflammatory cytokines, IL-1beta and TNF-alpha, and their up-regulation of adhesion molecules, ICAM-1, VCAM-1 and E-Selectin, in the pathogenesis of cerebral malaria (CM) is well established, the role of local cytokine release remain unclear. Immunohistochemistry (IHC) was used to compare the expression of ICAM-1, VCAM-1, E-Selectin, IL-1beta, TNF-a and TGF-beta at light microscopic level in cerebral, cerebellar and brainstem postmortem cryostat sections from 10 CM, 5 severe malarial anemia (SMA), 1 purulent bacterial meningitis (PBM), 2 non-central nervous system infections (NCNSI) and 3 non-infections (NI) deaths in Ghanaian children. Fatal malaria and Salmonella sepsis showed significantly higher vascular expression of all 3 adhesion molecules, with highly significant co-localization with sequestration in the malaria cases. However, there was negligible difference between CM and SMA. TGF-beta showed intravascular and perivascular distribution in all cases, but expression was most intense in the PBM case and CM group. TNF-alpha and IL-1beta showed prominent brain parenchymal staining, in addition to intravascular and perivascular staining, in only the PBM case and CM group. The maximal expression of all 6 antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation is a feature of fatal malaria and Salmonella sepsis, with adhesion molecule expression being highly correlated with sequestration. IL-1beta and TNF-alpha are upregulated in only cases with neurodegenerative lesions, whilst TGF-beta is present in all cases. Both cytokines and adhesion molecules were maximally upregulated in the cerebellar sections of the malaria cases.
Highlights
Despite technological advances and global economic development, malaria is still the parasitic disease responsible for the greatest number of deaths worldwide
Ten died of cerebral malaria (CM), five of severe malarial anaemia (SMA), one of purulent bacterial meningitis (PBM), two of non-central nervous system infections (NCNSI) and three of NI
We found that the presence of sequestered parasitized erythrocytes (PEs) was highly significantly associated with the expression of intercellular adhesion molecule (ICAM)-1 (P = 3.1 X 10-16), vascular cell adhesion molecules (VCAM)-1 (P = 1.2 X 10-12) and E-selection (P = 6.1 X 10-16) [degrees of freedom = 1] in the fatal malaria cerebral vessels (Table 2)
Summary
Despite technological advances and global economic development, malaria is still the parasitic disease responsible for the greatest number of deaths worldwide. Malaria parasites infects between 300 to 500 million people, causing up to 2 million deaths globally per year (mostly children in sub-Saharan Africa) from complications of primarily cerebral malaria (CM) and severe malarial anaemia (SMA) [1]. CM, characterised by seizures and loss of consciousness, is an important complication of Plasmodium falciparum infection with mortality rate of 15-20% [2]. Despite this high mortality rate, the pathogenic mechanisms of CM have not been well elucidated. The unavailability of infected human specimens and suitable animal models has hindered a thorough understanding of the pathogenesis
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