Glial activation and matrix metalloproteinase release in cerebral malaria

Abstract

Although neurological symptoms associated with cerebral malaria (CM) are largely reversible, recent studies suggest that lasting neurological sequelae can occur. This may be especially true for children, in whom persistent deficits include problems with memory and attention. Because the malaria parasite is not thought to enter the brain parenchyma, lasting deficits are likely related to factors including the host response to disease. Studies with a rodent model, and with human postmortem tissue, suggest that glial activation occurs with CM. In this review, the authors will highlight studies focused on such activation in CM. Likely causes will be discussed, which include ischemia and activation of blood brain barrier endothelial cells. The potential consequences of glial activation will also be discussed, highlighting the possibility that glial-derived proteinases contribute to structural damage of the central nervous system (CNS). Of note, for the purposes of this focused review, glial activation will refer to the activation of astrocytes and microglial cells; discussion of oligodendroglial cells will not be included. In addition, although events thought to be critical to the pathogenesis of CM and glial activation will be covered, a comprehensive review of cerebral malaria will not be presented. Excellent reviews are already available, including Coltel et al (2004; Curr Neurovasc Res 1: 91-110), Medana and Turner (2006; Int J Parasitol 36: 555-568), and Hunt et al (2006; Int J Parasitol 36: 569-582).

Matrix Metalloproteinase-9 and Haemozoin: Wedding Rings for Human Host andPlasmodium falciparumParasite in Complicated Malaria

“…These molecules have not been studied yet in human malaria. However, in CM murine models, MMP-2 mRNA and protein were upregulated in brain [18] and MMP-7 mRNA was increased in liver but not in brain [18], whereas MMP-7 protein was increased in brain [19]. …”

“…In the last decade, growing evidence on involvement of MMPs in falciparum malaria became available: human postmortem studies showed enhanced protein levels of MMP-1 in brains of CM patients [15], whereas MMP-8 was found increased in plasma of severe malaria patients [16]; additionally, activation of the human MMP-9 gene by P. falciparum has been reported in microarray studies on whole blood from children with malaria [17]. Interestingly, a role for MMPs during malaria is suggested also by evidence from nonhuman models of CM: in the brain of mice infected by P. Berghei ANKA, the etiological agent of murine CM, increased MMP-2, MMP-7, and MMP-9 levels, and pro-MMP-9 activation were found [18, 19]. …”

Analysis of the Neuroinflammatory Response to TLR7 Stimulation in the Brain: Comparison of Multiple TLR7 and/or TLR8 Agonists

“…N euroinflammation, including astrogliosis and production of proinflammatory cytokines and chemokines, is a common finding following viral, bacterial, and parasitic infections of the CNS in both children and adults (1)(2)(3)(4)(5)(6)(7)(8)(9). Neuroinflammatory responses are also observed in autism, Alzheimer's disease, and other neurological diseases of unknown etiology (10 -14).…”

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

“…Although differences between human and mouse pathology require cautious interpretation, observations in mouse models of experimental CM (ECM) show glial cell activation in the brain1213. There are not many studies analysing microglia during ECM, one of them has shown that depletion of cells expressing the chemokine receptor, CX3CR1, which includes microglia, during a PbA infection suggests that they may not play a decisive role in ECM, although they can interact with T cells14.…”