Dangerous liaisons: molecular basis for a syndemic relationship between Kaposi’s sarcoma and P. falciparum malaria

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.

Beyond Comorbidity: A Critical Perspective of Syndemic Depression and Diabetes in Cross‐cultural Contexts

“…This is because there is a risk of using syndemics as a heuristic, much like comorbidity, without critical review of the social, cultural, and economic factors that may shape the convergence of two diseases. What's at stake is an uncritical application of syndemic theory to the interpretation of disease clusters in public health and medicine (e.g., Conant and Kaleeba ), instead of pushing the health sciences to recognize the role of social factors in disease clustering. In other words, if syndemics is used to describe disease clusters in lieu of comorbidity, then there is potential that the syndemics construct will lose its fundamental tenet of scrutinizing the underlying role of social and political–economic processes in disease clustering among the poor.…”

The Manifesto of Pharmacoenosis: Merging HIV Pharmacology into Pathocoenosis and Syndemics in Developing Countries

“…HIV and malaria together account for about one million deaths globally every year, the latter being the third cause of HIV-related morbidity where these infections geographically overlap, with an overall co-prevalence of 23–29% and reaching coinfection prevalence of up to 72% in certain sub-Saharan areas [ 22 , 23 ]. While malaria could fuel HIV viral replication [ 24 ], Kaposi Sarcoma development [ 25 ], sexual and mother-to-child HIV transmission [ 26 ], and progression to AIDS [ 27 ], HIV has been suggested to increase malaria-associated mortality [ 28 ], placental involvement [ 29 ], parasite biomass, and the selection of antimalarial resistance [ 30 ]. As an example, mathematical models showed that in a small area of Kenya, malaria–HIV co-infection (MHC) has been responsible for 8500 and 980,000 excess in HIV and malaria infections since 1980, with an excess prevalence of 2.1% and 5.1%, respectively [ 31 ].…”

Co-infections and Pathogenesis of KSHV-Associated Malignancies

“…Furthermore, person-to-person transmission of KSHV could be facilitated by the bites of female Anopheles mosquitoes along with the transmission of malarial parasites. While experimental evidences demonstrating direct molecular mechanisms of interactions between KSHV and malarial parasite are lacking; Conant et al (2013) have proposed an interesting potential molecular link between malarial infection and KSHV reactivation. In malaria, the parasite-infected red blood cells (IRBCs) are sequestered from the peripheral circulation by adherence to microvascular endothelium of various organs.…”

“…CD36 is the main host endothelial cell receptor that mediates the adherence of IRBCs ( Gowda et al, 2013 ). Conant et al (2013) found that cross-linking of CD36 with a recombinant peptide derived from CD36 binding domain of pfEMP-1 antigen could revoke KSHV latency, presumably through activation of some of the signal transduction pathways that lead to an activation of KSHV-RTA promoter.…”