Malaria parasites target the hepatocyte receptor EphA2 for successful host infection

Abstract

Invasion of a suitable host hepatocyte by mosquito-transmitted Plasmodium sporozoites is an essential early step in successful malaria parasite infection. Yet, precisely how sporozoites target their host cell and facilitate productive infection remains largely unknown. Here, we found that the hepatocyte EphA2 receptor was critical for establishing a permissive intracellular replication compartment, the parasitophorous vacuole. Sporozoites productively infected hepatocytes with high EphA2 expression and deletion of EphA2 protected mice from liver infection. Lack of host EphA2 phenocopied the lack of the sporozoite proteins P52 and P36. Our data suggests that P36 engages EphA2, which is likely to be a key step to establish the permissive replication compartment.

The s48/45 six-cysteine proteins: mediators of interaction throughout the Plasmodium life cycle

“…Similar results were reported for PfΔP36 parasites in hepatocyte invasion assays in vitro, where parasite developmental arrest occurred early inside the host cell (VanBuskirk et al, 2009). Moreover, rapid clearance of PyΔP36 parasites from mouse livers has been recently described (Kaushansky et al, 2015). P36 (together with P52, Section 4.2) is critical for the establishment and/or maintenance of the parasitophorous vacuole during invasion as PyΔP36 parasites can enter hepatocytes but then are observed free in the cytoplasm of the host cell (Labaied et al, 2007; Ploemen et al, 2012).…”

“…Although there was abundant evidence that P36 is important for successful invasion of hepatocytes by sporozoites, the exact role of the protein had not been determined. However, a recent study points towards the interaction of P36 with host EphA2, a hepatocyte-expressed receptor tyrosine kinase that naturally binds GPI-anchored EphrinA1 to mediate cell-cell interactions (Kaushansky et al, 2015). This is an intriguing finding in light of the structural similarity of s48/45 domains with the Ephrin fold.…”

“…This is an intriguing finding in light of the structural similarity of s48/45 domains with the Ephrin fold. Although binding of P36 to EphA2 was not directly demonstrated, the work showed that recombinant P36 interfered with EphrinA1 binding to EphA2, indicating an interaction (Kaushansky et al, 2015). The importance of EphA2 in pre17 erythrocytic infection was corroborated by the observation that EphA2 knockout mice were dramatically less susceptible to sporozoite infection compared with wildtype mice and that sporozoites require hepatocytes with high expression of EphA2 to support invasion with parasitophorous vacuole formation (Kaushansky et al, 2015).…”

“…Although binding of P36 to EphA2 was not directly demonstrated, the work showed that recombinant P36 interfered with EphrinA1 binding to EphA2, indicating an interaction (Kaushansky et al, 2015). The importance of EphA2 in pre17 erythrocytic infection was corroborated by the observation that EphA2 knockout mice were dramatically less susceptible to sporozoite infection compared with wildtype mice and that sporozoites require hepatocytes with high expression of EphA2 to support invasion with parasitophorous vacuole formation (Kaushansky et al, 2015). It is tempting to hypothesize that the structural similarities between the host Ephrin fold and parasite s48/45 domains have been exploited by the parasite to allow interaction with Eph receptors for host cell engagement.…”

Vaccines to Accelerate Malaria Elimination and Eventual Eradication

“…These cells are recognized and bound by the amino-terminal region of CSP, mediating a signal for hepatocyte invasion (Coppi et al 2007). Hepatocyte membranebound CD81 is one important receptor for sporozoites (Silvie et al 2003), and EphA2, which associates with sporozoite proteins P52 and P36, is another (Kaushansky et al 2015). Intrahepatocytic replication commences inside the PV.…”