A new study from MIT offers a possible explanation for why some people are more likely to experience a more severe, and potentially fatal, form of malaria. According to a paper published in PLOS Pathogens today , natural killer cells (NK cells) fail to turn on the genes necessary to effectively destroy malaria-infected red blood cells in some patients.
In previous research, Jianzhu Chen, one of the senior authors of the paper, and his colleagues used humanized mice to investigate the roles of NK cells and macrophages in malaria infection. When they removed human NK cells from the mice and infected them with malaria, the quantity of parasites in the blood was much greater than in mice with NK cells. This did not happen when they removed human macrophages, suggesting that NK cells are the most important first-line defenders against malaria. They also found that in about 25% of the human blood samples they used, the NK cells did not respond to malaria at all.
In the new paper, they set out to try to find out why that was the case. To do that, they sequenced the RNA of NK cells before and after they encountered malaria-infected red blood cells. This allowed the researchers to identify a small number of genes that get turned on in malaria-responsive NK cells but not in nonresponsive cells. Among these genes was one that codes for a protein called MDA5, which was already known to be involved in helping immune cells such as NK cells and macrophages recognize foreign RNA. Further studies revealed that malaria-infected red blood cells secrete microvesicles that carry pieces of RNA from the malaria parasite. The studies also showed that NK cells absorb these microvesicles. If MDA5 is present, the NK cell is activated to kill the infected blood cell.
Chen and his colleagues also showed that they could activate the nonresponsive NK cells by treating them with a synthetic molecule called poly I:C, which is structurally similar to double-stranded RNA. For poly I:C to be effective, the researchers had to package it into liposomes, which allow it to enter cells just like the RNA-carrying microvesicles do.
The researchers also found a correlation between the levels of MDA5 in the NK cells and the disease severity experienced by the patients who donated the blood samples. Next, they hope to take cells from human patients and use them to further examine this correlation in humanized mice, and also to explore whether treating the mice with poly I:C would have the same beneficial effect they saw in cells grown in a lab dish.