RT Journal Article
SR Electronic
T1 Type I IFN promotes pathogenic inflammatory monocyte maturation during H5N1 infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.10.475751
DO 10.1101/2022.01.10.475751
A1 Slim Fourati
A1 David Jimenez-Morales
A1 Judd Hultquist
A1 Max W. Chang
A1 Christopher Benner
A1 Nevan Krogan
A1 Lars Pache
A1 Sumit Chanda
A1 Rafick-Pierre Sekaly
A1 Adolfo García-Sastre
A1 Melissa B. Uccellini
YR 2022
UL http://biorxiv.org/content/early/2022/01/11/2022.01.10.475751.abstract
AB Ly6Chi inflammatory monocytes show high IFN responses, and contribute to both protective and pathogenic functions following influenza virus infection. In order to understand the significance of IFN responses in this subset, we examined monocytes during infection with a lethal H5N1 virus that induces high levels of IFN and a low-pathogenicity H1N1 virus that induces low levels of IFN. We show that H5N1 infection results in early recruitment of high numbers of Ly6Chi monocytes and induction of chemokines and Ifnb1. Using unbiased transcriptomic and proteomic approaches, we also find that monocytes are significantly enriched during H5N1 infection and are associated with chemokine and IFN signatures in mice, and with severity of symptoms after influenza virus infection in humans. Recruited Ly6Chi monocytes subsequently become infected in the lung, produce IFN-β, and mature into FasL+ monocyte-derived cells (FasL+MCs) expressing dendritic cell markers. Both Ccr2-/- and Faslgld mice are protected from lethal infection, indicating that monocytes contribute to pathogenesis. Global loss of type I and type III IFN signaling in Stat2-/- mice results in loss of monocyte recruitment, likely reflecting a requirement for IFN-dependent chemokine induction. Here we show that IFN is not directly required for monocyte recruitment on an IFN-sufficient background, but is required for maturation to FasL+MCs. Loss of IFN signaling skews to a Ly6Clo phenotype associated with tissue repair, suggesting that IFN signaling in monocytes is a critical determinant of influenza virus pathogenesis.Competing Interest StatementThe authors have declared no competing interest.