Comprehensive immune profiling reveals IFN-? signaling in T cells mediates parasite phagocytosis in a rodent malaria model : Bulk RNA-seq

Pulmonary manifestations are life-threatening complications of malaria. To elucidate the immune landscape underlying malaria-associated lung pathology, we performed comprehensive transcriptomic analyses using a rodent malaria model. We identified that IFN-? signaling specifically in T cells is a critical regulator of lung pathology. Our data demonstrate that the disruption of IFN-? signaling in T cells results in reduced pulmonary parasite load and attenuated lung injury by enhancing T cell-monocyte interactions. Notably, this enhanced interaction promotes the expansion of a specific proinflammatory monocyte subset characterized by CD8 and Ly6C expression. This CD8+ Ly6C+ monocyte population exhibits significantly higher phagocytic capacity compared to its CD8- counterpart. Our study highlights the complex immune network induced by Plasmodium infection and reveals the essential role of the T cell-IFN-? signaling axis in modulating monocyte-mediated parasite clearance and lung pathology. Overall design: To systematically investigate the dynamics of the lung immune microenvironment during malaria-associated lung pathology, we performed a longitudinal transcriptomic analysis of lung tissues in a rodent malaria model. A total of 28 lung samples were sequenced, spanning six critical phases of infection: 3, 5, 7, 9, 11, and 13 days post-infection (dpi), with naïve, uninfected lung tissues serving as the baseline control. This high-resolution time-course design allows for the characterization of the transition from early inflammatory recruitment to advanced lung pathology. By integrating these data with genetic models (e.g., T cell-specific IFN-? signaling deficiency), this study provides a comprehensive resource for identifying key regulatory modules and cellular interactions—specifically the T cell-monocyte axis—that drive parasite clearance and tissue damage.