Influenza infection causes extensive immunopathology; few therapies are effective against this type of lung injury. Our published work shows that circadian rhythms confer a time-of-day specific protection from Influenza A Virus (IAV) infection through immune modulation. Our immunophenotyping studies showed NK cells as a key mediator of circadian protection from IAV. Rhythmicity in the NK cell numbers in the lung and circulation suggests that the recruitment of NK cells is controlled by the circadian clock. Depletion of NK cells or blocking the downstream signaling of the NK cell-secreted cytokine, IL10 worsened outcomes from IAV in the circadian context. To distinguish NK cell-intrinsic clock mechanisms from extrinsic circadian influences over this population,we generated a model wherein the clock is disrupted in the NK cells, Ncr1cre+ Bmal1fl/fl (Bmal1ΔNK).Bmal1ΔNKlungs had more leukocytes, but fewer NK cells in the uninfected state, and after infection, had 3-fold higher mortality, worse immunopathology, but fewer NK cells than WT littermates. Single cell RNA sequencing of sorted pulmonary NK cells from both Bmal1ΔNK and WT littermates revealed that the NK cell clock may be relevant to not only regulation of host immune response but also lung repair processes during recovery from IAV. In summary, NK cells mediate circadian regulation of outcomes in IAV through the regulation of acute inflammation and chronic repair.
NK cell intrinsic clock in the regulation of host response to influenza infection
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Poster and Podium (Block Symposium)
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Date: May 4 Presentation Time: 11:30 AM to 12:45 PM Room: Exhibit Hall F1