Protective coinfection: influenza reprograms myeloid cells to limit CD8 T cell-mediated malaria pathology

Malaria-associated acute lung injury (MA-ALI) is a life-threatening complication of malaria driven by pathogenic CD8 T cell responses with no effective pharmaceutical interventions. Here, we show that co-infection with non-lethal influenza/A/HKx31 (X31) protects mice from malarial pulmonary vascular leak and death. X31 co-infection drove the expansion of Ly6C⁺ monocyte-derived alveolar macrophages, which inhibited pathogenic CD8 T cells in a contact-dependent manner. Moreover, in vivo blockade of monocytic myeloid cells with gemcitabine eliminated the protective phenotype. Protection occurred independently of Parasite burden and did not require type I interferon signaling. Instead, co-infected pulmonary CD8 T cells exhibited broad transcriptional reprogramming and impaired inflammatory cytokine production. Our findings demonstrate that virus-induced myeloid cells suppress pulmonary CD8 T cells to prevent lung immunopathology in severe malaria. This work suggests that therapeutics that expand suppressive myeloid cells should be considered for adjunctive therapy for MA-ALI.

CD8 T cells; Malaria; Plasmodium; arginase; co-infection; immune suppression; influenza; lung injury; malaria-associated acute lung injury; myeloid cells.