Influenza-induced suppressive alveolar macrophages protect against malarial immunopathology during coinfection 3547

Abstract Description Severe cerebral and pulmonary vascular damage by CD8 T cells remains a major challenge in malaria, which kills >600,000 people annually. Coinfections can significantly alter disease progression by changing the immune kinetics. Our objective was to investigate influenza coinfection, which is highly understudied in malaria. We infected C57BL/6J mice with Plasmodium berghei NK65-Edinburgh (PbE), which causes fatal pulmonary vascular leak within 6-10 days, and a sub-lethal dose of Influenza/A/X31. Surprisingly, coinfection significantly prolonged survival (20.8 vs. 9.0 days). Despite maintaining equal parasitemia as the malaria-only group, the coinfected group failed to develop the same lung pathology. We profiled the anti-influenza immune response by flow cytometry and identified an alveolar macrophage (AM) subset expressing inhibitory markers such as Arg1, iNOS, and PD-L1. This population is not induced by PR8, which also does not provide a protective phenotype during Plasmodium coinfection. In vitro suppression assays demonstrated that these AMs dampen CD8 activation and proliferation in a contact-dependent manner. Gemcitabine depletion of AMs showed that they are required for protection. These findings reveal an unprecedented coinfection dynamic where influenza-induced AMs modulate the anti-malarial response to prevent immunopathology. Ongoing work is exploring alternate strategies to induce these protective AMs, offering new potential treatments in malarial pulmonary injury. Funding Sources Supported by NIH F31HL172638-01, NIH T32AI138945-06A1, NIH R21AI185994. Topic Categories Viral Immunology (VIR)