Editors' ChoiceMalaria

You (don’t) give me fever

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Science Translational Medicine  18 Sep 2019:
Vol. 11, Issue 510, eaaz2897
DOI: 10.1126/scitranslmed.aaz2897


A baseline transcriptional signature in peripheral blood is associated with protection from febrile malaria in children.

Malaria remains one of the major lethal infectious diseases worldwide, with almost half a million deaths each year, but factors contributing to disease susceptibility remain poorly understood. Tran et al. conducted a prospective 3-year study in Malian children, who showed different abilities to control fever and parasitemia after documented Plasmodium falciparum infection. Children with the malaria-protective hemoglobin S allele were excluded. They chose children 6 to 11 years old, the age when antimalarial immunity is usually acquired in this population. Using a hypothesis-generating, systems biology approach, they integrated whole-blood transcriptomics with flow cytometric analyses together with plasma cytokine and antibody profiles. They identified three distinct groups according to infection responses: immune children controlling both fever and parasitemia, a delayed fever group initially controlling fever and parasitemia but later-on showing progressive disease, and an early fever group that was unable to control fever or parasitemia.

The authors found that immune children harbored several markers suggesting an activated immune state even before infection, consisting of monocyte and platelet activation, interferon signaling, T helper (TH) cell activation, and B cell enrichment, together with better reactivity of P. falciparum-specific IgG than nonimmune children. In contrast, enhanced activation of the cell cycle regulator p53 and a TH2-prone immune environment characterized the delayed fever group. Thus, p53 activation supposedly dampens P. falciparum–induced inflammation without impacting parasitemia (previous mouse models suggest it might still help to reduce the burden of liver stage P. falciparum infections). The authors speculate that there might be a contribution of prior helminth infection in shaping this kind of preinfection immune activation pattern, but rates of helminth infection were too low in this population to draw definitive conclusions.

This study comprehensively investigates immune responses to P. falciparum infections in subjects protected from severe malaria symptoms, limiting interindividual variability due to its longitudinal, prospective nature, thus resulting in an enhanced ability to detect infection-driven differences between patient groups. Future investigations using similar research design in combination with single cell transcriptomics might further elucidate malaria-protective factors, to better understand dynamics of this still insufficiently studied disease.

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