Molecular Mechanism of Host Specificity in Plasmodium falciparum Infection

Abstract

Plasmodium falciparum sporozoites invade liver cells in humans and set the stage for malaria infection. Circumsporozoite protein (CSP), a predominant surface antigen on sporozoite surface, has been associated with the binding and invasion of liver cells by the sporozoites. Although CSP across the Plasmodium genus has homology and conserved structural organization, infection of a non-natural host by a species is rare. We investigated the role of CSP in providing the host specificity in P. falciparum infection. CSP from P. falciparum, P. gallinaceum, P. knowlesi, and P. yoelii species representing human, avian, simian, and rodent malaria species were recombinantly expressed, and the proteins were purified to homogeneity. The recombinant proteins were evaluated for their capacity to bind to human liver cell line HepG2 and to prevent P. falciparum sporozoites from invading these cells. The proteins showed significant differences in the binding and sporozoite invasion inhibition activity. Differences among proteins directly correlate with changes in the binding affinity to the sporozoite receptor on liver cells. P. knowlesi CSP (PkCSP) and P. yoelii CSP (PyCSP) had 4,790-and 17,800-fold lower affinity for heparin in comparison to P. falciparum CSP (PfCSP). We suggest that a difference in the binding affinity for the liver cell receptor is a mechanism involved in maintaining the host specificity by the malaria parasite.Malaria infection in humans is initiated with the bite of an infectious female mosquito, which inject sporozoites of Plasmodium species into the circulation. These sporozoites rapidly bind and invade liver cells and undergo rapid multiplication, leading to the release of thousands of infective merozoites (1). Out of more than 20 well documented and characterized species of Plasmodium that cause malaria in various vertebrates, only four species viz., P. falciparum, P. vivax, P. malariae, and P. ovale infect humans. It is intriguing that, although numerous parasite surface antigens involved in infectivity and pathogenesis possess inter-species homology and have been identified in numerous humans, rodents, and simian Plasmodium species (2-5), the parasite maintains its host specificity and non-natural host infections are rare. In laboratory conditions, it is possible to infect Aotus monkeys with human parasites (6, 7). Most of these infections have been induced by inoculating erythrocytic stage parasites or salivary gland-isolated sporozoites in splenectomized animals and with a parasite load not seen in malaria endemic areas (7,8

Isolation and characterization of heparan sulfate from various murine tissues

“…Furthermore, these highly charged liver HS chains also appear to act as receptors for pathogens such as dengue virus [36] and malaria circumsporozoite [37]. It is interesting to note that mice, also sensitive to malaria, have a similar highly sulfated liver HS [38].…”

Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains

“…Native CSP interacts with heparan sulfate proteoglycans on the surface of hepatocytes during the invasion process (18,21,22), but the precise region mediating binding has not been defined. We tested whether heparin binding by PpCSP, in which the N terminus of the native CSP protein is deleted to E74, and EcCSP, which has the near full CSP protein sequence, was affected and determined that both EcCSP and PpCSP bound heparin, but EcCSP had a slightly higher binding affinity, as assessed by the increased NaCl concentration required for elution (Fig.…”

Role of Glycosaminoglycans in Cellular Communication

“…The liver HS of these species differ and may be partially responsible for this species specificity. 64 Insects are known to produce HS. The structure of HS from the midgut and salivary glands of Anopholes may be similar to that of human liver HS.…”