Inside Scoop on Outside Proteins

Abstract

Invasion into red blood cells is an essential step in the life cycle of parasites that cause human malaria. Antibodies targeting the key parasite proteins in this process are important for developing a protective immune response. In the current issue, Boyle and colleagues provide a detailed examination of Plasmodium falciparum invasion and specifically illuminate the fate of surfaceexposed parasite proteins during and immediately after invasion.H uman malaria remains a leading cause of death and disease worldwide. Recent estimates suggest that there were 225 million cases of malaria in 2009, with more than 1 million deaths in 2010 (1, 2). The parasite Plasmodium falciparum causes the most severe forms of malaria. Resistance to existing antimalarial medications is a constant and continually emerging hurdle to the effective treatment of malaria. At the same time, efforts to find a broadly effective vaccine providing sustained protection have not yet been successful. For these reasons, and many more, a more intricate understanding of the molecular details of the parasite life cycle is needed. Knowledge of the molecular mechanism of parasite invasion, replication, and egress will hopefully provide new targets for antimalarial therapeutics and vaccines. The work described in this issue by Boyle and colleagues (3) provides a new layer of complexity in our understanding of P. falciparum invasion into human red blood cells (RBCs). PLASMODIUM FALCIPARUM: AN EVASIVE INVADERAfter a susceptible person is bitten by an infected female Anopheles mosquito, P. falciparum sporozoites travel to the liver and invade hepatic cells. Inside the hepatocyte, the sporozoite differentiates and produces thousands of RBC-invasive merozoites (4). Once released from the protected intracellular environment, a merozoite has a very limited window of time to find and invade a RBC or risks clearance by the host reticuloendothelial system and/or inactivation by antibodies. Several elegant studies have described the basic steps of merozoite invasion of (Fig. 1). The predominant model of parasite invasion proposes that the merozoite reversibly binds the surface of the RBC via multiple lowaffinity interactions between parasite-expressed merozoite surface proteins (MSPs) and RBC surface proteins (e.g., Band 3) or heparin-like glycosaminoglycans (13-15). The invading merozoite must reorient itself to bring the apical end, with its associated apical organelles (rhoptries, micronemes, and dense granules), into direct contact with the RBC surface. Reorientation likely requires the action of P. falciparum apical membrane protein 1 (PfAMA1) (7). Interestingly, the "receptor" for PfAMA1 is another parasite protein, RON2, that is injected into the host side of the RBC membrane (16,17). Following reorientation, the merozoite forms an irreversible attachment to the RBC, known as the tight junction, which is made in part from the PfAMA1-RON2 interaction. The formation of the tight junction likely involves multiple interactions between parasite ligands located i...

The Application of ‘Elite Interviewing’ Methodology in Transdisciplinary Research: a Record of Process and Lessons Learned during a 3-Year Pilot in Urban Planetary Health Research

“…overspecialisation within academia and the prevailing disconnection between academia and the real world and a growing demand for 'knowledge brokers' and 'blended professionals', alongside a similar challenge to co-production: the 'dark side of knowledge brokerage'. [21,[48][49][50][51][52][53] Objectives and Phases…”