The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups. However, the basis for this lower susceptibility to malaria by the Fulani is unknown. The incidence of classic malaria resistance genes are lower in the Fulani than in other sympatric ethnic populations, and targeted SNP analyses of other candidate genes involved in the immune response to malaria have not been able to account for the observed difference in the Fulani susceptibility to P.falciparum. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection. eLife digest There is a huge international effort to combat malaria, but even today almost half a million people die from the disease each year, mostly young children in Africa. Malaria infections are caused by the parasite Plasmodium , which is spread by mosquitoes. The Fulani are an ethnic group of people from West Africa that are naturally better at fighting malaria infections with the most dangerous form of the parasite, Plasmodium falciparum . Fulani show fewer symptoms of malaria and carry fewer parasites when they are infected. They also have fewer cases of sickle cell disease, a condition that is known to protect against malaria. Yet, no one understands what it is that makes Fulani more resistant to malaria than other people, such as people of other ethnic groups that live in the same region of West Africa but who do not intermarry with the Fulani. Past studies that looked at likely genes, such as those involved in the immune response, could not find any differences between the Fulani and people who have a normal susceptibility to malaria. Quin, Bujila et al. performed a pilot study to look at the activity of all the genes in immune cells from Fulani people who had become naturally infected with P. falciparum to see which genes are switched on or off after an infection. If some genes are used differently in the Fulani compared to other ethnic groups, then it is likely that these genes are responsible for the Fulani’s more effective immune response to P. falciparum. First, Quin, Bujila et al. looked for chemical markers that are naturally added to DNA to influence the activity of nearby genes, and used other methods to determine which genes are switched on and at what level. Unexpectedly, for those markers looked at, no difference was found between the ethnic groups investigated. However, the other experiments did show that in a certain type of immune cell in the Fulani over 1,000 genes become notably more active, or less active, after P. falciparum infection. These cells, called monocytes, are important for the immune system’s first line of defence, which begins the attack against an infection and alerts the rest of the immune system. Lastly, inflammation is a common part of the body’s immune response to many parasites. When Quin, Bujila et al. measured the level of inflammatory molecules, they found that Fulani have higher levels of molecules that promote inflammation than other ethnic groups. Together these results suggest that a group of genes in the monocytes of Fulani are set in a ‘primed’ state, which helps monocytes to drive the fight against P. falciparum more effectively. The cause for the heightened primed state remains unclear, but previous studies looking into bacterial and fungal infections have shown early infections can prime the immune system to promote more inflammation during a second infection. These new findings suggest that such processes might also occur for malaria infections, and so might represent a new avenue of research in the quest for better treatments for malaria.
【저자키워드】 Transcriptome, Innate immunity, Human, monocyte, malaria, Inflammasome, P. falciparum, Fulani,