Mechanistic evaluation of the role of circadian rhythms in acute lung injury and subsequent recovery

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Project Summary Our overall aim is to define the mechanisms underlying the circadian regulation of acute lung injury and subsequent recovery. Our published work shows that circadian rhythms confer a time of day specific protection from Influenza A Virus (IAV) infection. Mice infected at dawn had 3-fold better survival than those infected at dusk. While, we cannot clinically control the time of exposure to IAV, these data suggest that altering the circadian health of the host could affect outcomes. In fact, disrupting circadian rhythms genetically in mice, by deleting the core clock gene, Bmal1, worsened mortality from IAV. Further proof of the translational relevance of our mechanistic work came from our analyses of the UK biobank which revealed that disrupted circadian rhythms was an independent risk factor for Influenza related hospitalization. Severe influenza infection is characterized by extensive immunopathology and dysplastic lung repair and regeneration, often independent of viral burden. Both vaccines and anti-viral agents have limited efficacy. The current proposal addresses this need in the field by exploring a novel target—circadian rhythms as determinant of outcomes in IAV. Since the last submission, we have generated exciting preliminary data that shows that disruption of the AT2 clock is associated with (a) worse acute mortality, immunopathology and necroptosis and (b) delayed recovery in vivo and poor regeneration on organoid assays. Our overall goals are to: (1) Test the hypothesis that the disruption of the AT2 clock leads to a pro-inflammatory state at baseline that is further exacerbated by IAV infection, thereby worsening necroptosis. (2) To test the hypothesis that the circadian clock contributes to lung regeneration through Wnt- responsive regulation of the cell cycle via the Axin2+ epithelial niche. Our approach employs tissue specific circadian knock-out models induced in adulthood, circadian sampling throughout 24hrs, other genetic/environmental models of circadian disruption and tools form lung regenerative biology, customized to the circadian context. I have also gathered an outstanding team of collaborators and consultants with expertise in cell death, circadian bioinformatics, lung regeneration and virology. Elucidating these mechanisms is the critical next step towards modulating the host circadian rhythms for therapeutic purposes. While, we use influenza as our model, the principles uncovered thus, should be generalizable to other viral conditions of the lung.