Plasmodium vivax Liver and Blood Stages Recruit the Druggable Host Membrane Channel Aquaporin-3

Dora Posfai,Steven P Maher,Camille Roesch,Amélie Vantaux,Kayla Sylvester,Julie Péneau,Jean Popovici,Dennis E Kyle,Benoît Witkowski,Emily R Derbyshire

doi:10.1016/j.chembiol.2020.03.009

Dora Posfai, Steven P Maher + Show 8 more

Open Access

https://doi.org/10.1016/j.chembiol.2020.03.009

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Abstract

SummaryPlasmodium vivax infects hepatocytes to form schizonts that cause blood infection, or dormant hypnozoites that can persist for months in the liver before leading to relapsing blood infections. The molecular processes that drive P. vivax schizont and hypnozoite survival remain largely unknown, but they likely involve a rich network of host-pathogen interactions, including those occurring at the host-parasite interface, the parasitophorous vacuole membrane (PVM). Using a recently developed P. vivax liver-stage model system we demonstrate that host aquaporin-3 (AQP3) localizes to the PVM of schizonts and hypnozoites within 5 days after invasion. This recruitment is also observed in P. vivax-infected reticulocytes. Chemical treatment with the AQP3 inhibitor auphen reduces P. vivax liver hypnozoite and schizont burden, and inhibits P. vivax asexual blood-stage growth. These findings reveal a role for AQP3 in P. vivax liver and blood stages and suggest that the protein may be targeted for therapeutic treatment.

Highlights

The Plasmodium parasite that causes malaria led to over 200 million cases of the disease in 2018 (WHO, 2019)
Host Membrane Protein AQP3 Localizes to the P. vivax Liver-Stage Parasitophorous Vacuole Few host factors are known to be important for P. vivax liverstage development despite compelling evidence that Plasmodium depends on its host throughout infection
At 8 dpi, no AQP3 signal above background was observed in uninfected primary human hepatocytes (PHH), but protein was detected in P. vivax-infected PHH (Figure S1A)

Summary

Introduction

The Plasmodium parasite that causes malaria led to over 200 million cases of the disease in 2018 (WHO, 2019). Liver schizonts have been shown to produce merozoites expressing biological markers for gametocyte development, indicating possible direct transmission from the liver after a single round of infection of liver merozoites into reticulocytes (Roth et al, 2018a, 2018b). Such a scenario would indicate ‘‘silent’’ transmission occurring before malaria symptoms and treatment with antimalarials. Over the first several days of liver infection the sporozoite may form a hypnozoite which grows slightly before becoming biologically quiescent (Krotoski et al, 1982; Mikolajczak et al, 2015). The P. vivax liver stage is an important unmet area of therapeutic intervention

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