Influenza A Virus Infection Instructs Hematopoiesis to Megakaryocyte-lineage Output and hyper-reactive platelets

Respiratory tract infections remain among the deadliest communicable diseases worldwide. Severe cases of viral lung infections are often associated with a cytokine storm and alternating platelet numbers. We report that hematopoietic stem and progenitor cells (HSPC) sense a non-systemic influenza A virus (IAV) infection via inflammatory cytokines. Irrespective of antiviral treatment or vaccination, at a certain threshold of IAV titer in the lung CD41-positive HSCs enter the cell cycle while endothelial protein C receptor-positive CD41-negative HSCs reside in quiescence. CD41-positive HSCs are the source of megakaryocytes and rapid platelet production, while their multi-lineage reconstitution potential was reduced. This emergency megakaryopoiesis was thrombopoietin independent and attenuated in IAV-infected interleukin 1-deficient mice. Newly produced platelets during IAV infection were immature and hyper-reactive. After viral clearance, HSC quiescence was re-established. Our study reveals that non-systemic viral respiratory infection has an acute impact on HSCs via inflammatory cytokines to counter act IAV-induced thrombocytopenia.