Influenza A virus-induced interferon-alpha production by myeloid dendritic cells and macrophages requires productive infection.

Severe Influenza A virus (IAV) infections are accompanied by a cytokine storm with type I interferon (IFN) as the main driver. Besides epithelial cells, alveolar macrophages and infiltrating dendritic cells are target cells for IAV. IAV are classified into different strains, defined by their major surface glycoproteins haemagglutinin (HA) and neuraminidase (NA). So far, 19 HA subtypes and 11 NA subtypes are known. However, it is not well understood, why infection with certain IAV strains results in a cytokine storm with severe outcomes, while other IAV strains only cause mild infections. In order to address this question, we investigated six seasonal and five highly pathogenic avian IAV (HPAIV) strains using primary human ex vivo isolated plasmacytoid dendritic cells (pDC), as well as in vitro differentiated myeloid dendritic cells (mDC) and macrophages (type M1 and M2). Our data reveal that IFN-α production by mDC and macrophages but not by pDC is dependent on productive infection with the respective IAV strain. In contrast to IFN-α production in pDCs, IFN-α production by mDC as well as M1 and M2 macrophages is mainly induced by HPAIV strains, indicating that other immune cells apart from pDC might have an impact on induction of type I interferon as the main driver of the cytokine storm in the patients and the severity of the associated disease. Our findings may provide insights into the viral tropism and host response upon infection with different IAV strains and improve the understanding of the accompanied pathogenesis.