Single-cell profiling reveals immunoregulation of artemisinin on CD8+GZMB+ T cells via JAK2-STAT3 in malaria-infected mice

Public summary

* Single-cell transcriptomics landscape of the peripheral blood, liver, and spleen of malaria-infected mice.

* The heterogeneous immune responses across tissue and cell types before and after artemisinin treatment.

* CD8+GZMB+ T cells exert an inflammatory response that drives liver injury during Plasmodium berghei infection.

* Artemisinin modulates the cytotoxicity of CD8+GZMB+ T cells via the JAK2-STAT3 pathway.

Abstract

Malaria, a pervasive and devastating disease, is characterized by systemic complications and dysregulated host immune responses to Plasmodium infection. Artemisinin derivatives, particularly artesunate (ART), are a cornerstone in malaria treatment strategies. Although the precise immunomodulatory mechanisms remain unclear, ART not only kills parasites but also impacts host immune homeostasis. In this study, we employed single-cell RNA sequencing to characterize the cellular landscape of 241,837 cells from multiple murine tissues (including liver, spleen, and peripheral blood) upon Plasmodium berghei ANKA (PbA) infection and after ART treatment. Meanwhile, we observed significant transcriptomic shifts across diverse immune cell types, with the liver exhibiting the most pronounced changes in response to PbA infection. Notably, CD8+GZMB+ T lymphocytes, characterized by elevated cytokine and cytotoxic module scores, play a pivotal role in driving hepatic injury. Furthermore, ART modulated this pathogenic subtype via the JAK2-STAT3 pathway, reducing its frequency and mitigating its inflammatory response. Our research provides a valuable dataset resource for exploring malaria immunopathogenesis and elucidates a novel immunoregulatory mechanism of ART within the infected host.