The latest Paper of the Month for Parasitology is Rosetting revisited: a critical look at the evidence for host erythrocyte receptors in Plasmodium falciparum rosetting

Malaria claims the lives of almost half a million people worldwide every year, and millions more suffer the consequences of severe disease, including coma and severe anaemia. Despite huge advances in the reduction of case numbers and mortality in the past decade, the World Health Organisation recently issued a stark warning that “Progress has stalled” (WHO Malaria Report 2018), and there is a pressing need for new approaches to reduce malaria deaths. Although effective anti-parasite treatments such as Artemisinin Combination Therapies are increasingly available worldwide, we still have little to offer in terms of “add-on” therapies designed to relieve the underlying pathological processes that cause life-threatening disease. In order to develop such therapies, we need a better understanding of the host-parasite interactions that lead to the severe forms of malaria.

P. falciparum rosettes – clusters of infected (parasites stained white) and uninfected red blood cells can be seen in this microscopy image.

Rosetting is one such pathological process; it is defined as the adhesion of two or more uninfected red blood cells to a parasite-infected red cell leading to clumps of cells called rosettes (see figure and movie).  This is thought to cause obstruction in tiny blood vessels throughout the body, leading to the severe symptoms such as coma seen in cerebral malaria. If we can identify how the infected and uninfected red cells stick together, we can potentially figure out how to break the rosettes apart, and this could be used to treat people with severe malaria.

In our review, we delve deep into the mechanisms of rosetting, focusing mainly on the “host” side of the interaction by describing the contribution of surface molecules on uninfected red blood cells. We consider the potential role of various molecules ranging from ABO blood group sugars, through to proteins such as the glycophorins and heparin-like glycosaminoglycans. One of our main conclusions is that we still lack good evidence that the currently proposed rosetting receptors are essential for multiple different Plasmodium falciparum isolates; the key puzzle piece is still a mystery. We’ve made some suggestions about how we might go about finding this missing piece, and how identifying it could lead to a treatment to reduce deaths and severe malaria disease in the future.

The full article is available Open Access.

Movie: the video clip shows P. falciparum rosettes (cell clusters) under flow in a perfusion system in vitro. The rosettes are strong and remain intact under shear forces equivalent to those experienced in vivo. The potential for the rosettes to obstruct tiny blood vessels, contributing to malaria pathology via hypoxia and tissue damage, can be appreciated. Video courtesy of Dr Yvonne Adams, Dr Fiona McQuaid and Prof Alex Rowe.

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