Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis

Malaria is a life-threatening disease transmitted by mosquitoes infected with Plasmodium parasites. Part of the parasite life cycle happens inside human red blood cells. The surface of an infected red blood cell is coated with parasite proteins, which attract the attention of white blood cells called monocytes. These immune cells circulate in the bloodstream and use a process called phagocytosis to essentially 'eat' any infected cells they encounter. However, the monocytes cannot always reach the infected cells. Some of the proteins made by the parasites make the infected red blood cells stickier than normal. This allows the infected red blood cells to surround themselves in a protective cage of uninfected red blood cells. Known as “rosettes” because of their flower-like shape, these cages seem to protect the infected cells from attack by the immune system. Lee et al. noticed that adding white blood cells to parasite-infected red blood cells made them clump together more, but it was unclear exactly how and why this happened. To find out, Lee et al. took fluid from around monocytes grown in the laboratory and added it to red blood cells infected with Plasmodium parasites. This made the cells clump together, suggesting that something in the fluid may potentially be alerting the parasites to impending immune attack. The fluid contained almost 700 different molecules, and Lee et al. narrowed down their investigations to the five most likely candidates. Interfering with the activities of these five proteins revealed that one – a protein IGFBP7 – not only alerted the parasites but also helped them to form the rosettes. It turns out that the parasites appear to use IGFBP7 like a bridge, linking it to two other human proteins to stick red blood cells together. Once the rosettes had formed, the monocytes were unable to eat the infected blood cells by themselves. Instead several monocytes had to work together as a team to consume the whole rosette. Further research is now needed to shed light on this interaction between malaria parasites and human cells. Such research would be particularly relevant in the clinical setting, since some previous studies has linked the forming of rosettes to the severity of disease for malaria.