Influenza virus-induced pathogenesis is largely determined by viral virulence and host immune responses. We establish infected mouse models with mild, moderate, or severe pathogenic outcomes to address the relationships among high viral loads, heavy leukocyte infiltration and cytokine storm. Herein, we find an excessive accumulation of CCR2+ inflammatory monocytes upon highly pathogenic influenza virus infection. Mechanistically, impaired clearance of highly virulent virus prolongs production of type I IFN, which results in the massive production of the CCR2 ligands, CCL2, CCL7 and CCL12. Notably, CCR2+ inflammatory monocytes are the major producers of IFNbeta and CCR2 ligands in the inflitrating leukocytes. Blockage of IFNAR significantly decreases infiltrating CCR2+ inflammatory monocytes. Furthermore, recruitment of CCR2+ inflammatory monocytes from bone marrow to lung associates with the level of CCR2 ligands. Thus, uncontrolled viral replication in the late stage of infection sustains type I IFN production and then amplifies the loop of CCL2, CCL7, CCL12 and CCR2, which is one of the reasons to serious outcome of influenza infection.
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