TNF family members and malaria: Old observations, new insights and future directions
Introduction
Members of the tumor necrosis factor (TNF) superfamily (TNFSF), together with the corresponding TNF receptor (TNFR) superfamily (TNFRSF) members, form a network of important signaling pathways that have a wide-range of functions in the innate and adaptive immune systems. In malaria research, many studies have focused on the role of TNF and its receptors in the generation of protective immune responses, as well as its contribution to the development of severe malaria (SM) syndromes. Interest in TNF first arose when serum containing TNF was shown to inhibit the multiplication of Plasmodium vinckei in mice (Clark et al., 1981). Its role in generating malaria pathology was highlighted by reports of higher levels of TNF in the sera of cerebral malaria (CM) patients (Grau et al., 1989a), an observation supported by earlier studies in an experimental mouse model of CM (ECM) (Grau et al., 1987, Grau et al., 1989b). Since these pioneering studies, a number of TNFSF and TNFRSF family members have been implicated in both the generation of protective immunity and development of disease. In this review, we will first outline our current understanding about the interactions between TNFSF and TNFRSF members, and then discuss recent findings relating to the roles of these molecules in malaria, with particular emphasis on their impact on the development of CM.
Section snippets
TNFSF and TNFRSF members
More than 20 receptor-ligand systems have now been described for the TNFSF and TNFRSF members (reviewed in Ware, 2005). TNFSF members are type II transmembrane glycoproteins that share similarities in the TNF-homology region, the region involved in receptor binding (Gruss, 1996). TNFSF members include TNF, lymphotoxin (LT)-α, LTβ, CD40L, TRAIL, OX40L, CD27L, CD30L, Fas ligand (FasL; CD95L) and BAFF. LTα3 and endothelial cell-growth inhibitor are the only members exclusively secreted from cells,
Human-malaria co-evolution: Impact on TNFSF gene selection
Studies to date suggest that Plasmodium falciparum and humans have had intense interactions for thousands of years and, for this reason, it has been hypothesised that malaria has imposed strong selective pressure on the human genome (Kun et al., 2001, Rich et al., 1998). Interestingly, high frequencies of alleles associated with resistance to malaria can be found in geographical locations that once had high malaria endemicity (Sotgiu et al., 2008). Hill et al. have summarized current opinions
TNFR2 and regulatory T cells in malaria
Regulatory T (Treg) cells are a CD4+ T cell subset that express both the forkhead/winged helix transcription factor Foxp3 and CD25 (IL-2Rα) (reviewed in Vignali et al., 2008). Treg cells have well-defined immunosuppressive abilities important for the maintenance of tolerance to self antigens and restricting autoimmune diseases, as well as regulating immune responses to pathogens and other foreign stimuli. Natural Treg cells are produced in the thymus, but inducible Treg cells have also been
LIGHT, LTβR and ECM
Following the report that LTα is involved in the development of ECM (Engwerda et al., 2002), studies were carried out to determine the LTα complex responsible. Initial studies showed that LTβR-deficient mice failed to develop ECM, while LTβ-deficient mice were partially protected, suggesting a role for LTα1β2 in ECM pathogenesis (Togbe et al., 2008). However, these mice have deficiencies in secondary lymphoid organs, which may contribute to the level of protection achieved (Alimzhanov et al.,
Concluding comments
The TNFSF and TNFRSF members clearly have important roles in both protecting people from malaria, as well as contributing to CM pathogenesis. Genetic approaches to understand the relevance of these molecules to malaria susceptibility suggest that different effects might be found in different populations, depending on selective pressures during evolution. Future deep sequencing of genes encoding these molecules is likely to provide further clues to the importance of these molecules in malaria.
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Present address: Department of Pathobiology, University of Pennsylvania, 380 S. University Avenue, Philadelphia, PA 19104, USA.