Host Scavenger Receptor SR-BI Plays a Dual Role in the Establishment of Malaria Parasite Liver Infection

Rodrigues, Cristina S.; Hannus, Michael; Prudêncio, Miguel; Martin, Cécilie; Gonçalves, Lígia Antunes; Portugal, Sílvia; Epiphânio, Sabrina; Akinc, Akin; Hadwiger, Philipp; Jahn‐Hofmann, Kerstin; Röhl, Ingo; Gemert, Geert-Jan van; Franetich, Jean‐François; Luty, Adrian J. F.; Sauerwein, Robert W.; Mazier, Dominique; Koteliansky, Victor; Vornlocher, Hans‐Peter; Echeverri, Christophe J.; Mota, Maria M.

doi:10.1016/j.chom.2008.07.012

Cited by 158 publications

(164 citation statements)

References 29 publications

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“…Huh7 cells at about 60% confluence were treated in 24-well plates with the different compounds and were infected 1 h later with GFP-expressing P. berghei sporozoites obtained from freshly dissected mosquito salivary glands at a multiplicity of infection of ϳ0.3. Fluorescence-activated cell sorting (FACS) analysis at 4 h and 48 h after infection was performed as previously described (26,29).…”

Section: Parasites Cells and Micementioning

confidence: 99%

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Capela

Cabal

Rosenthal

et al. 2011

Antimicrob Agents Chemother

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It is widely accepted that the struggle against malaria depends on the development of new strategies to fight infection. The "magic bullet" thought to be necessary to reach eradication should not only provide treatment for all Plasmodium spp. that infect human red blood cells but should also eliminate the replicative and dormant liver forms of the parasite. Moreover, these goals should ideally be achieved by using different mechanisms of action so as to avoid the development of resistance. To that end, two hybrid molecules with covalently linked primaquine and artemisinin moieties were synthesized, and their effectiveness against the liver and blood stages of infection was compared in vitro and in vivo with those of the parent compounds. Both hybrids displayed enhanced in vitro activities, relative to those of the parent compounds, against Plasmodium berghei liver stages. Both compounds were about as potent as artemisinin against cultured Plasmodium falciparum (50% inhibitory concentration [IC 50 ], ϳ10 nM). When used to treat a murine P. berghei infection, one of the molecules displayed better efficacy than an equimolar mixture of the parent pharmacophores, leading to improved cure and survival rates. These results reveal a novel approach to the design and evaluation of antimalarials based on the covalent combination of molecules acting on different stages of the parasite life cycle.

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Section: Parasites Cells and Micementioning

confidence: 99%

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Capela

Cabal

Rosenthal

et al. 2011

Antimicrob Agents Chemother

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“…Candidate-based approaches have revealed several host cell receptors that facilitate sporozoite infection of hepatocytes, such as the tetraspanin CD81 (10), scavenger receptor B1 (SR-BI) (11,12), and heparin sulfate proteoglycans (HSPGs) (13,14). However, none of these receptors are entirely essential for infection in vivo, arguing that an unbiased investigation aimed at identifying novel hepatocyte receptors required for sporozoite infection is needed.…”

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confidence: 99%

Susceptibility to Plasmodium yoelii Preerythrocytic Infection in BALB/c Substrains Is Determined at the Point of Hepatocyte Invasion

et al. 2015

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bAfter transmission by Anopheles mosquitoes, Plasmodium sporozoites travel to the liver, infect hepatocytes, and rapidly develop as intrahepatocytic liver stages (LS). Rodent models of malaria exhibit large differences in the magnitude of liver infection, both between parasite species and between strains of mice. This has been mainly attributed to differences in innate immune responses and parasite infectivity. Here, we report that BALB/cByJ mice are more susceptible to Plasmodium yoelii preerythrocytic infection than BALB/cJ mice. This difference occurs at the level of early hepatocyte infection, but expression levels of reported host factors that are involved in infection do not correlate with susceptibility. Interestingly, BALB/cByJ hepatocytes are more frequently polyploid; thus, their susceptibility converges on the previously observed preference of sporozoites to infect polyploid hepatocytes. Gene expression analysis demonstrates hepatocyte-specific differences in mRNA abundance for numerous genes between BALB/cByJ and BALB/cJ mice, some of which encode hepatocyte surface molecules. These data suggest that a yet-unknown receptor for sporozoite infection, present at elevated levels on BALB/cByJ hepatocytes and also polyploid hepatocytes, might facilitate Plasmodium liver infection.

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“…This was evidenced by the lack of infection of CD81-deficient mouse hepatocytes by P. yoelii sporozoites (10) and by the inhibition of P. yoelii and P. falciparum sporozoite invasion by antibodies or siRNA targeting mouse and human CD81, respectively (10,11). Another host cell surface protein, the scavenger receptor class B type I (SR-BI), also plays a role during sporozoite invasion (12,13). SRBI regulates CD81 expression level as well as membrane cholesterol (12), which is known to modulate CD81 ability to support Plasmodium infection (11).…”

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confidence: 99%

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Charrin

Yalaoui

Bartosch

et al. 2009

Journal of Biological Chemistry

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Invasion of hepatocytes by Plasmodium sporozoites is a prerequisite for establishment of a malaria natural infection. The molecular mechanisms underlying sporozoite invasion are largely unknown. We have previously reported that CD81 is required on hepatocytes for infection by Plasmodium falciparum and Plasmodium yoelii sporozoites. CD81 belongs to the tetraspanin superfamily of transmembrane proteins. By interacting with each other and with other transmembrane proteins, tetraspanins may play a role in the lateral organization of membrane proteins. In this study, we investigated the role of the two major molecular partners of CD81 in hepatocytic cells, CD9P-1/EWI-F and EWI-2, two transmembrane proteins belonging to a novel subfamily of immunoglobulin proteins. We show that CD9P-1 silencing increases the host cell susceptibility to P. yoelii sporozoite infection, whereas EWI-2 knock-down has no effect. Conversely, overexpression of CD9P-1 but not EWI-2 partially inhibits infection. Using CD81 and CD9P-1 chimeric molecules, we demonstrate the role of transmembrane regions in CD81-CD9P-1 interactions. Importantly, a CD9P-1 chimera that no longer associates with CD81 does not affect infection. Based on these data, we conclude that CD9P-1 acts as a negative regulator of P. yoelii infection by interacting with CD81 and regulating its function.Malaria remains the most important parasitic human disease, responsible for nearly one million deaths each year (1). Plasmodium natural infection is initiated by the inoculation of sporozoites in the host by a female Anopheles mosquito.Within the first hours of infection the motile sporozoites reach the liver and invade hepatocytes, where they further differentiate into a replicative exo-erythrocytic form (EEF) 5 that will ultimately give rise to thousands of merozoites that initiate the pathogenic erythrocytic cycle. Plasmodium sporozoites invade hepatocytes actively by forming a membrane-bound compartment called the parasitophorous vacuole (PV), where the parasite resides for further intracellular development (2, 3). The nature of the molecular interactions mediating sporozoite invasion still remains elusive. Two well-characterized sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related adhesive protein, are known to interact with the liver heparan sulfate proteoglycans (HSPGs) (2, 3). HSPGs play a role in the initial sequestration of the sporozoites in the liver sinusoids (4, 5), and activate sporozoites for productive invasion, leading to proteolytic processing of the circumsporozoite protein (6). Two sporozoite proteins, P36 and P36p/ P52, were shown to play a major role during infection of hepatocytes (7-9). Both belong to a Plasmodium-specific family characterized by the presence of domains with six conserved cysteines, but their precise function during sporozoite invasion and/or maintenance of the PV early after invasion remains unknown.To date, the only host molecule clearly identified as being essential for sporozoite invasion is CD81. ...

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Host Scavenger Receptor SR-BI Plays a Dual Role in the Establishment of Malaria Parasite Liver Infection

Cited by 158 publications

References 29 publications

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Design and Evaluation of Primaquine-Artemisinin Hybrids as a Multistage Antimalarial Strategy

Susceptibility to Plasmodium yoelii Preerythrocytic Infection in BALB/c Substrains Is Determined at the Point of Hepatocyte Invasion

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

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