Innate immune activation is a major determinant for morbillivirus attenuation in primary cells 2716

Abstract Description The live-attenuated measles virus (MeV) vaccine is one of the most efficacious vaccines ever developed and has the potential to eradicate MeV from the human population. While having been administered to millions of children over the past 60 years, the molecular mechanisms of its attenuation remain elusive. To determine these mechanisms, we have performed a comparative study of wild type (WT) and vaccine strain MeV infections in peripheral blood mononuclear cells (PBMCs) from human donors, the natural target cells of MeV. We performed in vitro growth kinetics, high-parameter spectral flow cytometry, next generation RNA-seq, and protein analyses. We found that the vaccine strain specifically activated cell intrinsic innate immunity signaling cascades causing a strong type-I interferon (IFN) signature. This resulted in 100-fold reduced titers of vaccine compared to WT virus. Surprisingly, while MeV vaccine infected B and T cells expressing the natural MeV receptor CD150 with similar efficiency as the WT virus, we found a subset of CD150-negative, CD11b+CD11c+CD123+ myeloid cells to become infected with the vaccine strain. We propose that these innate immune cells are highly specialized in pathogen sensing and prime the IFN response preventing vaccine from productive replication and generation of progeny virus in PBMCs. We currently investigate whether altered cell entry or innate immune control mechanisms are the underlying cause of attenuation. Funding Sources Supported by the German Research Foundation (DFG) Collaborative Research Center (SFB) 1021 (Project number 197785619/B12), internal funding of the German Ministry of Health, and by Mayo Clinic. Topic Categories Viral Immunology (VIR)