Abstract
Sporozoite forms of the malaria parasite Plasmodium 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. In previous studies, two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the Scavenger Receptor BI (SR-BI), were shown to play an important role during entry of Plasmodium sporozoites into hepatocytic cells. In contrast to HCV entry, which requires both CD81 and SR-BI together with additional host factors, CD81 and SR-BI operate independently during malaria liver infection, as sporozoites can use CD81 and/or SR-BI, depending on the Plasmodium species, to invade hepatocytes. However, the molecular function of CD81 and SR-BI during parasite entry remains unknown. Another HCV entry factor, the Ephrin receptor A2 (EphA2), was recently reported to play a key role as a host cell entry factor during malaria liver infection. Here, we investigated the contribution of EphA2 during CD81-dependent and SR-BI-dependent sporozoite infection. Using small interfering RNA (siRNA) and antibodies against EphA2, combined with direct detection of parasites by flow cytometry or microscopy, we show that blocking EphA2 has no significant impact on P. yoelii or P. berghei host cell infection, irrespective of the entry route. Thus, our findings argue against an important role of EphA2 during malaria liver infection.
Highlights
Despite some progress in malaria control over the world, 212 million cases still occurred globally in 2016, causing 429 000 deaths, mostly among children under 5 years old in Africa [1]
Since we have shown that Plasmodium sporozoites use distinct host entry pathways depending on the parasite species, we explored the implication of Ephrin receptor A2 (EphA2) using different hepatocytic cell types infected with P. yoelii or P. berghei sporozoites
We did not observe any correlation between EphA2 and CD81 surface expression levels (Pearson coefficient R2 = 0,263), indicating that the higher susceptibility of EphA2high cells reported by Kaushanksy et al is not linked to higher expression of CD81, which is essential for both P. yoelii and P. berghei sporozoite infection in this cellular model [14,21]
Summary
Despite some progress in malaria control over the world, 212 million cases still occurred globally in 2016, causing 429 000 deaths, mostly among children under 5 years old in Africa [1]. An effective vaccine would be a powerful tool to eradicate the disease. To this end, the liver stage of infection is a suitable target as it is an obligatory gateway for parasite replication. The liver stage of infection is a suitable target as it is an obligatory gateway for parasite replication After their inoculation into the skin by infected Anopheles mosquitoes, Plasmodium sporozoites rapidly migrate to the liver using gliding motility and cell traversal activity. They first traverse hepatocytes before invading them and developing into exo-erythocytic forms (EEFs), surrounded by a parasitophorous vacuole membrane (PVM).
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