Despite major eradication efforts over the past century, malaria remains a significant world-wide health burden. Plasmodium vivax poses the greatest obstacle to malaria eradication due to its ability to form dormant stages within the liver, called hypnozoites. Hypnozoites can reactivate weeks to years after the initial infection, leading to relapses, and can only be targeted by two licensed drugs with extensive side effects and toxicity that limits their use. Models of disease prevalence suggest that even a modest reduction of hypnozoite abundance in the liver could make a major impact on the spread of disease. All Plasmodium parasites that have been extensively studied have been shown to rely on specific host signaling events for invasion and development through liver stage infection. These host factors represent potential targets for host-based interventions. Unfortunately, there remains a dearth of knowledge regarding the host factors that permit Plasmodium vivax liver stages to persist and develop, in large part because of technical challenges associated with growing the parasite and then monitoring host signaling events in rare infected cells. Here, we propose to overcome these challenges by using two approaches, kinase regression and digital spatial profiling, to interrogate host-driven phosphosignaling in P. vivax-infected hepatocytes, including those that harbor hypnozoites. If successful, our approach will identify host kinases that are necessary for P. vivax developing and dormant liver stages, as well as phosphosignaling that is altered by infection. These data will dramatically enhance our understanding of host factors that regulate Plasmodium vivax liver infection, and in doing so provide insight into the cellular niche that promotes liver-stage parasite development and dormancy. In addition to enhancing the understanding of this largely mysterious process, this information could inform host-directed therapies, which represent a novel approach to targeting dormant malaria parasites.
Malaria kills approximately half of a million people annually. One of the major hurdles to malaria eradication is the ability of Plasmodium vivax to form hypnozoites, dormant liver stages that can remain within the host for years and lead to relapses. This proposal seeks to assess host factors that change upon, and are necessary for, P. vivax developing and dormant parasites, with the long-term goal of using this information to eliminate relapsing malaria.
