Plasmodium berghei EXP-1 interacts with host Apolipoprotein H during Plasmodium liver-stage development

Abstract

The first, obligatory replication phase of malaria parasite infections is characterized by rapid expansion and differentiation of single parasites in liver cells, resulting in the formation and release of thousands of invasive merozoites into the bloodstream. Hepatic Plasmodium development occurs inside a specialized membranous compartment termed the parasitophorous vacuole (PV). Here, we show that, during the parasite's hepatic replication, the C-terminal region of the parasitic PV membrane protein exported protein 1 (EXP-1) binds to host Apolipoprotein H (ApoH) and that this molecular interaction plays a pivotal role for successful Plasmodium liver-stage development. Expression of a truncated EXP-1 protein, missing the specific ApoH interaction site, or down-regulation of ApoH expression in either hepatic cells or mouse livers by RNA interference resulted in impaired intrahepatic development. Furthermore, infection of mice with sporozoites expressing a truncated version of EXP-1 resulted in both a significant reduction of liver burden and delayed blood-stage patency, leading to a disease outcome different from that generally induced by infection with wildtype parasites. This study identifies a host-parasite protein interaction during the hepatic stage of infection by Plasmodium parasites. The identification of such vital interactions may hold potential toward the development of novel malaria prevention strategies. malaria | Plasmodium liver stages | host-parasite interaction | ApoH | EXP-1

Quantitative Proteomic Analysis of Simian Primary Hepatocytes Reveals Candidate Molecular Markers for Permissiveness to Relapsing Malaria Plasmodium cynomolgi

“…These pathogens included Mycobacterium tuberculosis , Helicobacter pylori , Candida albicans , Leishmania spp., hepatitis C , and HIV‐1 . In addition, apolipoproteins were identified in this screen that have previously been reported to interact with the malaria parasite P. falciparum PFE1590w/ETRAMP and P. berghei parasitophorous vacuole membrane exported protein 1 (EXP‐1) during liver stage development . Squalene synthase, an essential host hepatocyte enzyme required for sterol production was also significantly up‐regulated in both FMD1 and SGD7.…”

“…Other studies have shown apolipoprotein as an important ligand for the high‐density lipoprotein and SR‐BI . Apolipoprotein also interacts with malaria parasite . Like ASGPR, apolipoprotein expression level was markedly high only in both FMD1 and SGD7 but not OMD7, suggesting a potential interaction with malaria‐relapsing species.…”

A crucial role for the C‐terminal domain of exported protein 1 during the mosquito and hepatic stages of thePlasmodium bergheilife cycle

“…EXP1 is also expressed by liver stage parasites (Sanchez, Rogers, Mellouk, & Hoffman, 1994) and localizes to the PVM, to which it is continuously transported throughout at least the first 30 hr of intrahepatic development (Hanson et al, 2013). We have recently shown that Plasmodium berghei (Pb) EXP1 binds to host Apolipoprotein H (ApoH) during the hepatic phase of infection and that this interaction plays a pivotal role throughout parasite development inside liver cells (Sa et al, 2017).…”

“…Pb/PfEXP1's topology includes an N-terminal (NT) domain (aa 1-75/1-79) that harbours a classical signal peptide (aa 1-23 ;Coppel et al, 1985); a putative catalytic domain that includes the Pf Arg70 residue and is presumed to be responsible for GST activity in blood stage parasites (Lisewski et al, 2014); an internal hydrophobic region typical of transmembrane anchor sequences (aa 75-97/79-101;Coppel et al, 1985); and a C-terminal (CT) domain (aa 97-166/101-162) that includes a C1 (aa 103-136/107-134) and a C2 (aa 137-166/135-162) region, as defined in Sa et al (2017). In both blood and liver parasite stages, EXP1 is proposed to be integrated into the PVM with the N-terminus facing the lumen of the PV and the C-terminus exposed to the host cell cytosol (Ansorge, Paprotka, Bhakdi, & Lingelbach, 1997;Gunther et al, 1991;Tribensky, Graf, Diehl, Fleck, & Przyborski, 2017).…”

“…We have previously shown that the C2 region of PbEXP1's CT domain mediates the interaction with, and internalisation of, host ApoH during the hepatic stage of infection (Sa et al, 2017). However, little is known about the role of each domain of this protein, including the CT domain in its entirety, on the various stages of the parasite's life cycle.…”