Abstract
Sporozoite forms of the Plasmodium parasite, the causative agent of malaria, are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. The molecular mechanisms involved during sporozoite invasion of hepatocytes remain poorly understood. Two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the scavenger receptor class B type 1 (SR-B1), play an important role during the entry of Plasmodium sporozoites into hepatocytes. In contrast to HCV entry, which requires both CD81 and SR-B1 together with additional host factors, CD81 and SR-B1 operate independently during malaria liver infection. Sporozoites from human-infecting P. falciparum and P. vivax rely respectively on CD81 or SR-B1. Rodent-infecting P. berghei can use SR-B1 to infect host cells as an alternative pathway to CD81, providing a tractable model to investigate the role of SR-B1 during Plasmodium liver infection. Here we show that mouse SR-B1 is less functional as compared to human SR-B1 during P. berghei infection. We took advantage of this functional difference to investigate the structural determinants of SR-B1 required for infection. Using a structure-guided strategy and chimeric mouse/human SR-B1 constructs, we could map the functional region of human SR-B1 within apical loops, suggesting that this region of the protein may play a crucial role for interaction of sporozoite ligands with host cells and thus the very first step of Plasmodium infection.
Highlights
Sporozoite forms of the Plasmodium parasite, the causative agent of malaria, are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood
Previous studies have shown that mice deficient for either CD81 or scavenger receptor class B type 1 (SR-B1) remain susceptible to P. berghei sporozoite infection[2, 3, 5], which could be explained by the mutual functional compensation between the two entry routes[4]
To test whether CD81 and SR-B1 are the only host factors permitting the entry of the parasite in murine hepatocytes, we analyzed the effect of CD81 neutralization in primary hepatocytes isolated from wild type (WT) or transgenic C57BL/6 J mice harboring a Cre-mediated SR-B1 gene inactivation in the liver[10]
Summary
Sporozoite forms of the Plasmodium parasite, the causative agent of malaria, are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. Despite progress in malaria control over the last two decades, Plasmodium parasites continue to cause more than 200 million cases every y ear[1] After their inoculation into the skin by infected Anopheles mosquitoes, Plasmodium sporozoites rapidly migrate through tissues and blood vessels to reach the liver, using active gliding motility and cell traversal activity. Whilst SR-B1 is the only known hepatocyte entry factor for P. vivax sporozoites, studying this parasite remains difficult, notably due to the limited access to infected mosquitoes. In this context, P. berghei provides an attractive model to investigate the role of SR-B1 during sporozoite infection. We took advantage of this functional difference to study the structural determinants of the SR-B1 receptor in Plasmodium invasion, using a structure-guided strategy based on chimeric constructs combining mouse and human SR-B1 domains
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