Influenza A virus infection instructs hematopoiesis to megakaryocyte-lineage output
Marcel G.E. Rommel,
Lisa Walz,
Foteini Fotopoulou,
Saskia Kohlscheen,
Franziska Schenk,
Csaba Miskey,
Lacramioara Botezatu,
Yvonne Krebs,
Iris M. Voelker,
Kevin Wittwer,
Tim Holland-Letz,
Zoltán Ivics,
Veronika von Messling,
Marieke A.G. Essers,
Michael D. Milsom,
Christian K. Pfaller,
Ute Modlich
Affiliations
Marcel G.E. Rommel
Research Group Gene Modification in Stem Cells, Division of Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Lisa Walz
Research Group Pathogenesis of Respiratory Viruses, Division Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Foteini Fotopoulou
Division of Experimental Hematology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), 69120 Heidelberg, Germany; Faculty of Biosciences, University of Heidelberg, 69120 Heidelberg, Germany
Saskia Kohlscheen
Research Group Gene Modification in Stem Cells, Division of Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Franziska Schenk
Research Group Gene Modification in Stem Cells, Division of Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Csaba Miskey
Research Group Transposition and Genome Engineering, Division of Medical Biotechnology, Paul-Ehrlich-Institute, 63225 Langen, Germany
Lacramioara Botezatu
Research Group Transposition and Genome Engineering, Division of Medical Biotechnology, Paul-Ehrlich-Institute, 63225 Langen, Germany
Yvonne Krebs
Research Group Pathogenesis of Respiratory Viruses, Division Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Iris M. Voelker
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institute, 63225 Langen, Germany
Kevin Wittwer
Research Group Pathogenesis of Respiratory Viruses, Division Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Tim Holland-Letz
Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Zoltán Ivics
Research Group Transposition and Genome Engineering, Division of Medical Biotechnology, Paul-Ehrlich-Institute, 63225 Langen, Germany
Veronika von Messling
Research Group Pathogenesis of Respiratory Viruses, Division Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Marieke A.G. Essers
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), 69120 Heidelberg, Germany; Division of Inflammatory Stress in Stem Cells, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
Michael D. Milsom
Division of Experimental Hematology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), 69120 Heidelberg, Germany
Christian K. Pfaller
Research Group Pathogenesis of Respiratory Viruses, Division Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany
Ute Modlich
Research Group Gene Modification in Stem Cells, Division of Veterinary Medicine, Paul-Ehrlich-Institute, 63225 Langen, Germany; Faculty of Medicine, Goethe University Frankfurt am Main, 60590 Frankfurt am Main, Germany; Corresponding author
Summary: Respiratory tract infections are 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 (HSPCs) 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 hematopoietic stem cells (HSCs) enter the cell cycle while endothelial protein C receptor-positive CD41-negative HSCs remain quiescent. Active CD41-positive HSCs represent the source of megakaryocytes, while their multi-lineage reconstitution potential is reduced. This emergency megakaryopoiesis is thrombopoietin independent and attenuated in IAV-infected interleukin-1 receptor-deficient mice. Newly produced platelets during IAV infection are immature and hyper-reactive. After viral clearance, HSC quiescence is re-established. Our study reveals that non-systemic viral respiratory infection has an acute impact on HSCs via inflammatory cytokines to counteract IAV-induced thrombocytopenia.
