scRNA-Seq reveals elevated interferon responses and TNF-α signaling via NFkB in monocytes in children with clinical malaria

Malaria causes significant morbidity and mortality worldwide, disproportionately impacting sub-Saharan Africa. Disease phenotypes associated with malarial infection can vary widely, from asymptomatic to life-threatening. To date, prevention efforts, particularly those related to vaccine development, have been hindered by an incomplete understanding of which factors impact host immune responses resulting in these divergent outcomes. Here, we conducted a field study in 224 malaria positive individuals (rapid diagnostic test - RDT) from a high transmission area in Ghana, to determine immunological factors associated with uncomplicated malaria "patients" compared to healthy individuals in the community "controls". Generally, the patients had higher parasite density levels although it had a negative correlation with age, suggesting that, is a key indicator of disease pathogenesis. We applied single-cell RNA-sequencing to compare the immunological phenotypes of 18,176 peripheral blood mononuclear cells (PBMCs) isolated from a subset of the patients and controls (n=11/224), matched on location, age, sex, and parasite density. On average, patients were characterized by a higher fractional abundance of monocytes and an upregulation of innate immune responses, including those to type I and type II interferons and tumor necrosis factor-alpha (TNF-) signaling via NF{kappa}B. Further, in the patients, we identified more putative interactions between antigen-presenting cells and proliferating CD4 T cells and naive CD8 T cells driven by MHC-I and MHC-II signaling pathways, respectively. Together, these findings highlight transcriptional differences between immune cell subsets associated with malaria that may help guide the development of improved vaccines and new therapeutic interventions for individuals residing in endemic areas.