High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria

Abstract

Although the roles played by systemic tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta), and their upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin, in the pathogenesis of human cerebral malaria (CM) are well established, the role of local cytokine release, in the brain, remains unclear. Immunohistochemistry was therefore used to compare the expression of ICAM-1, VCAM-1, E-selectin, IL-1beta, TNF and transforming growth factor beta (TGF-beta) at light-microscope level, in cryostat sections of cerebral, cerebellar and brainstem tissues collected, post-mortem, from Ghanaian children. Among the 21 children investigated were 10 cases of CM, five of severe malarial anemia (SMA), one of purulent bacterial meningitis (PBM), two of non-central-nervous-system infection (NCNSI) and three children who had no infection (NI) when they died. Parasitised erythrocytes were detected in all of the sections from the cases of fatal malaria (CM and SMA), and sequestered leucocytes were present in most of the sections from the CM cases (but none of the sections from the SMA cases). Significantly elevated vascular expression of all three adhesion molecules investigated was detected in the brains of the 15 cases of fatal malaria and one of the cases of NCNSI (a child with Salmonella septicaemia), and in the malaria cases this showed highly significant co-localization with the areas of erythrocyte sequestration. In terms of the levels of expression of ICAM-1, VCAM-1 and E-selectin, there were, however, negligible differences between the CM and SMA cases. Although TGF-beta showed intravascular and perivascular distribution in all the subjects, its expression was most intense in the PBM case and the CM group. Only in the sections from the PBM and CM cases did TNF and IL-1beta show prominent brain parenchymal staining, in addition to the intravascular and perivascular staining seen in all subjects. The highest observed expression of each of the six antigens studied was in the cerebellar sections of the malaria cases. Endothelial activation in the brain therefore appears to be a feature of fatal malaria and Salmonella sepsis, and in cases of fatal malaria is closely associated with leucocyte sequestration. In the present study, IL-1beta and TNF were only up-regulated in the brains of children with neurodegenerative lesions, whereas TGF-beta was present in all cases.

CXCL4 and CXCL10 Predict Risk of Fatal Cerebral Malaria

“…The discovery of a reliable laboratory test that accurately identifies individuals at risk of developing fatal CM would be a valuable tool. Human studies have revealed tight association between levels of specific chemokines and CM mortality [4,5,12,41,[43][44][45]67]. Thus, understanding the alterations in cytokine or chemokine homeostasis in CM patients will elucidate the underlying pathogenesis and identify potential predictive prognostic biomarkers for CM mortality.…”

The immunological balance between host and parasite in malaria

“…TNF levels increase with disease severity and are maximal in severe malaria patients, both with P. falciparum and P. vivax (Hemmer et al 1991(Hemmer et al , 1994Deloron et al 1994;Perlmann et al 1997;Holst et al 1999;Luty et al 2000;Perkins, Weinberg andKremsner 2000, Lyke et al 2004;Duarte et al 2007;Guiyedi et al 2007;Tchinda et al 2007;Raza et al 2013). Highest brain levels of TNF are observed in P. falciparum patients who died from cerebral pathology (Maneerat et al 1999;Armah et al 2005). Despite the pathogenic role of TNF in malaria pathology, deficiency of TNF or TNFR1 has no effect on murine CM (Hermsen et al 1997;Lucas et al 1997a,b;Engwerda et al 2002;Piguet, Kan and Vesin 2002a;Hansen et al 2004;Parekh et al 2006;Togbe et al 2008).…”

“…Neuronal ANG1 and ANG2 staining are associated with microhemorrhages, whereas no association is found with parasite sequestration. ICAM-1 is also increased in the cerebral endothelium of CM patients (Ockenhouse et al 1992;Turner et al 1994;Armah et al 2005), and may augment parasite sequestration (Bengtsson et al 2013). Also in P. vivax infections markers of endothelial activation are increased and correlate with severity and with peripheral parasitemia (Ohnishi 1999;Raza et al 2013;Gomes et al 2014).…”

Potential Serological Biomarkers of Cerebral Malaria

“…The pathogenesis of CM is still not well understood although it is clearly multifactorial, involving sequestration of P. falciparum infected erythrocytes to brain vasculature, triggering inflammatory cytokine responses and apoptotic pathway leading to a breach and dysfunction of the blood brain barrier, tissue damage and repair [26][27][28][29]. In an attempt to understand the pathogenesis of CM, our previous studies in Ghana [30] and India [31] for the first time revealed a striking association between the chemokine interferon inducible protein-10 (CXCL10-) and CM severity, suggesting that CXCL10 may be a biomarker for CM severity.…”