During blood-stage malaria, infection of red blood cells with Plasmodium falciparum leads to global metabolic changes in the host as a result of both the pathogen hijacking host metabolism for its own survival and proliferation, and host adaptation to the metabolic demands of an immune response to infection. However, the extent to which metabolic changes are associated with variation in host susceptibility to malaria is unknown. This study reports serum metabolome profiling of children naturally infected with P. falciparum in Burkina Faso, West Africa, revealing major changes in endogenous steroid levels with effects on adaptive immunity.
The most highly represented class among these 53 metabolites was endogenous steroids. The authors showed a statistically significant negative correlation between 13 steroids and the lymphocyte count during infection, which suggests that these steroids might have an inhibitory effect on the immune response. To investigate further, they generated 72 RNA-sequencing profiles from 36 Gouin children before and during infection. During infection, the transcript abundance of 1,649 genes correlated with levels of infection-associated pregnenolone and androgen steroids, as well as with parasitaemia. The most highly affected signalling pathways during infection were related to inhibition of T cell function, such as enrichment of PDL1 signalling and downregulation of CD28 and CD40LG. This was associated with changes in the expression levels of T helper cell surface marker and transcription factor genes. Further analysis focusing on pregnenolone sulfate showed a causal association between this steroid, changes in gene expression of 11 key regulators of lymphocyte activation and proliferation, and lymphocyte count during infection. In vitro, stimulated peripheral blood mononuclear cells from healthy donors had reduced T cell proliferation and cytokine production when treated with pregnenolone sulfate. The results suggest that increased steroid biogenesis during blood-stage malaria in Gouin children has an immunosuppressive effect.
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