Abstract
The most severe manifestations of malaria (caused by Plasmodium falciparum) occur as a direct result of parasitemia following invasion of erythrocytes by post-liver blood-stage merozoites, and during subsequent cyto-adherence of infected erythrocytes to the vascular endothelium. However, the disproportionate epidemiologic clustering of severe malaria with aggressive forms of endemic diseases such as Kaposi’s sarcoma (KS), a neoplasm that is etiologically linked to infection with KS-associated herpesvirus (KSHV), underscores the significance of previously unexplored co-pathogenetic interactions that have the potential to modify the overall disease burden in co-infected individuals. Based on recent studies of the mechanisms that P. falciparum and KSHV have evolved to interact with their mutual human host, several new perspectives are emerging that highlight a surprising convergence of biological themes potentially underlying their associated co-morbidities. Against this background, ongoing studies are rapidly constructing a fascinating new paradigm in which the major host receptors that control parasite invasion (Basigin/CD147) and cyto-adherence (CD36) are, surprisingly, also important targets for exploitation by KSHV. In this article, we consider the major pathobiological implications of the co-option of Basigin/CD147 and CD36 signaling pathways by both P. falciparum and KSHV, not only as essential host factors for parasite persistence but also as important mediators of the pro-angiogenic phenotype within the virus-infected endothelial microenvironment. Consequently, the triangulation of interactions between P. falciparum, KSHV, and their mutual human host articulates a syndemic relationship that points to a conceptual framework for prevalence of aggressive forms of KS in malaria-endemic areas, with implications for the possibility of dual-use therapies against these debilitating infections in resource-limited parts of the world.
Highlights
Plasmodium falciparum (Pf) malaria is one of the world’s leading health challenges, and at least two million people, mainly children below the age of 5 years, die each year from clinical complications of the disease (Snow et al, 2005)
PERSPECTIVES Infectious agents have long been implicated in the etiology of a variety of illnesses, and recent studies have examined the role of microbial co-infections in many disease settings, it is not known whether “cooperative pathogenesis” is sufficient to provide the driving force behind strategies in which co-pathogenic agents co-evolve and forge a state of forbearance with each other and with their shared host to advance mutually exclusive existential goals
Pf malaria has been linked to a variety of other infections that display co-pathogenic relationships with the parasite, notable among them being endemic Burkitt’s lymphoma (eBL) (Thorley-Lawson and Allday, 2008), but recent advances have revealed that many other important examples of these relationships do exist, and in most cases they provide a surprisingly informative conceptual window into how co-infections can modify each other’s disease course
Summary
Plasmodium falciparum (Pf) malaria is one of the world’s leading health challenges, and at least two million people, mainly children below the age of 5 years, die each year from clinical complications of the disease (Snow et al, 2005). The cognate erythrocyte receptor for PfRh5 was recently identified as CD147 [ known as Basigin (BSG), extracellular matrix metalloproteinase inducer (EMMPRIN), and leukocyte activation antigen, M6 (hereafter CD147); Crosnier et al, 2011]. This discovery is notable for the fact that the CD147/PfRh5 pair is essential for invasion of all laboratory-adapted and field strains of Pf, a crossstrain dependency that reveals opportunities for new anti-malarial therapies based on targeting this receptor/ligand interaction. A well-characterized host receptor that mediates cyto-adherence of most Pf isolates to the peripheral vasculature is human CD36 (Ockenhouse et al, 1989), other www.frontiersin.org
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