Distinct Immune Signatures are Associated with Exposure History in Human Malaria 2259590

Abstract Introduction As a surrogate to interrogating the diverse human immune response to natural malaria, we examined responses to four sequential controlled human malaria infection (CHMI) in malaria-naïve adults. Methods We used a multi-modal approach, integrating: 1) single-cell RNA-sequencing and Over-Representation Analysis (ORA) of naive peripheral blood mononuclear cells (PBMC) stimulated with Pf schizonts; 2) longitudinal plasma cytokine analysis; and 3) comparative cytokine profiling and Principal Component Analysis (PCA) of CHMI participants and Ghanaian children presenting with malaria illness. Results The naive monocyte response to Pf in vitro involves the simultaneous upregulation of pro-inflammatory cytokines and key regulatory molecules. ORA confirmed this paradox, showing co-activation of pro-inflammatory (NF-κB, TNF) and anti-inflammatory (IL-10) signaling pathways, alongside a decrease in host phagocytosis, cell metabolism, pathogen recognition and presentation. In vivo, both CHMI and natural Pf exposures trigger a similar paradoxical response. The maturation of the CHMI response is characterized by a progressively IL-10-dominant signature over four infections and a consistent post-infection increase in IL-18. PCA revealed a specific cytokine balance that differentiates the CHMI participants and Ghanaian children. Conclusion A paradoxical immune response was noted in both malaria-naïve and malaria-endemic individuals with PBMC expression of pro and anti-inflammatory cytokines. When compared to the CHMI participants response, the higher IL-10 and IL-18 and lower IL-21 and IL-4 response in Ghanaian children is consistent with high exposure in endemic areas modulating monocyte activation. Defining these different developmental and endpoint signatures is key for evaluating vaccine strategies and understanding naturally-acquired immunity. Funding Source 5R01AI177698-03 - National Institutes of Health (NIH) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)