Single-cell landscape of peripheral immune responses to fatal SFTS

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high fatality. Poor prognosis of SFTS has been associated with dysregulated host immunity; however, the immune patterns associated with pathophysiology involving SFTS exacerbation remain unclear. Here, we show that the single-cell landscape of peripheral immune responses is reprogrammed in SFTS and characterized by monocyte shift to an intermediate type along with complement activation, perturbation of plasmablast composition, and highly exhausted T cells, all correlated with lethal consequences. We identify the overexpression of interferon (IFN)-stimulated genes across most immune cell types after SFTSV infection, which are simultaneously related to older age, high viremia, and a hyperinflammatory response. A retrospective clinical study reveals no efficiency of IFN-α in treating SFTS. These data collectively support the intermediate monocytes and IFN-I-inducible plasmablasts to be major targets for SFTS virus infection, and they indicate the pivotal role of the IFN-I response in exacerbating hyperinflammation and lethal SFTS.