It is a plot out of a horror film: A dangerous parasite infiltrates our bodies and disguises itself in our cells, killing millions of people, many of them children. Unfortunately, this isn’t fiction—it describes malaria, a deadly disease spread by the bite of a Plasmodium-infected mosquito.
While the molecular mechanisms of Plasmodium infection are well-characterized, some continue to baffle scientists. One of them is rosetting, where parasite-infected red blood cells (RBCs) link to and surround themselves with uninfected RBCs. Scientists believe that these flower-like ‘rosettes’ allow infected RBCs to avoid immune detection, but the details remain unclear.
To better understand the mechanism of rosette formation in malaria, corresponding author Laurent Renia, Executive Director of A*STAR’s Infectious Diseases Horizontal Technology Center (ID HTC), assembled an international team comprising of scientists based in Singapore, New Zealand, Australia, France, Malaysia, Thailand and the UK.
“These flower-like rosette structures are stable and can withstand shear force as high as that of an artery. This means that these stable RBC clumps can hamper blood flow in our capillaries, leading to severe pathological consequences,” Renia said. “The rosettes also shield the parasites from being recognized and targeted by our immune system.”
The research team made two key discoveries: first, it was possible to increase rosette formation by adding white blood cells to parasite-infected patient samples; second, supernatant from cultured monocytes induced rosetting, implying that a factor secreted by white blood cells could induce rosette formation.
Mass spectrometry analysis and antibody neutralization assays identified a host protein secreted from monocytes that stimulates rosette formation: insulin-like growth factor binding protein 7 (IGFBP7). IGFBP7 acted as a key element of the bridge, linking infected and uninfected RBCs, and this process was facilitated by two soluble co-factors: von Willebrand Factor (VWF) and trombospondin 1(TSP-1).
The researchers call this new form of IGFBP7-mediated rosette formation ‘type II rosetting,’ to distinguish it from ‘classical rosetting,’ which occurs via direct interaction of host and parasite surface receptors. In phagocytosis studies, type II rosetting decreased the number of infected RBCs engulfed by immune cells, as it required the combined action of multiple phagocytes to engulf a single rosette.
“Now that we have deciphered an important role for rosetting phenomenon as an immune-evasion strategy by the parasites, we hope that this can inspire more researchers to solve the puzzles behind the pathogenesis of a parasitic infection that has cumulatively taken billions of lives since the beginning of civilization,” Renia said.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN), the Institute of Molecular and Cell Biology (IMCB) and the Institute of Medical Biology (IMB).