Biology subjects

Hiller, B.

Publications and source records attributed to Hiller, B..

3 recordsLinked to original sources

bioRxiv2022

Probing lung function at high spatiotemporal resolution using a novel crystal ribcage

Understanding the dynamic pathogenesis and treatment response in pulmonary diseases requires probing the lung at cellular resolution in real-time. Despite recent progress in intravital imaging, optical imaging of the lung during active respiration and circulation has remained challenging. Here, we introduce the crystal ribcage: a transparent ribcage that (i) allows truly multiscale optical imaging of the lung in health and disease from whole-organ to single cell, (ii) enables the modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal, and optogenetic interventions, and (iii) preserves the 3-D architecture, air-liquid interface, cellular diversity, and respiratory-circulatory functions of the lung. Utilizing these unprecedented capabilities on murine models of primary and metastatic lung tumors, respiratory infection, pulmonary fibrosis, emphysema, and acute lung injury we probed how disease progression remodels the respiratory-circulatory functions at the single alveolus and capillary levels. In cancer, we identified the earliest stage of tumorigenesis that compromises alveolar and capillary functions, a key state with consequences on tumor progression and treatment response. In pneumonia, we mapped mutual links between the recruited immune cells and the alveolar-capillary functions. We found that neutrophil migration is strongly and reversibly responsive to vascular pressure with implications for understanding of how lung physiology, altered by disease and anatomical location, affects immune cell activities. The crystal ribcage and its broad applications presented here will facilitate further studies of real-time remodeling of the alveoli and capillaries during pathogenesis of nearly any pulmonary disease, leading to the identification of new targets for treatment strategies.

bioengineering↗

bioRxiv2022

Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis

Cell-intrinsic response patterns control risks arising from genome-damage, preventing malignant transformation. The DNA sensor cyclic-GMP-AMP synthase (cGAS) has emerged as a new principle detecting genome damage, as it can be triggered by aberrant self-DNA. Stimulator of interferon genes (STING)-activation downstream of cGAS can drive cells into senescence or cell death and induces antiproliferative type I interferon (IFN) and pro-apoptotic tumor necrosis factor responses. Herein, we investigated how DNA damage-driven activation of cGAS/STING signaling impacts on hematopoiesis. Defective ribonucleotide excision repair (RER) in the hematopoietic system caused chromosomal instability as well as robust activation of the cGAS/STING/IFN axis, and compromised hematopoietic stem cell function, resulting in cytopenia and ultimately leukemia. Whereas loss of p53 largely rescued RER-deficient hematopoiesis at the cost of further accelerated leukemogenesis, the additional inactivation of cGAS, STING or type I IFN signaling had no detectable effect on blood cell generation and leukemia development. Moreover, cGAS-deficient hematopoiesis showed unaltered responses to spontaneous or acute DNA damage. Our data demonstrate that the cGAS/STING pathway is dispensable for the hematopoietic system coping with chronic or acute DNA damage and does not protect against leukemic transformation in the absence of RER.

cell biology↗

bioRxiv2021

Fibroblast growth factor-9 expression in airway epithelial cells amplifies the type I interferon response and alters influenza A virus pathogenesis

Influenza A virus (IAV) preferentially infects conducting airway and alveolar epithelial cells in the lung. The outcome of these infections is impacted by the host response, including the production of various cytokines, chemokines, and growth factors. Fibroblast growth factor-9 (FGF9) is required for lung development, can display antiviral activity in vitro, and is upregulated in asymptomatic patients during early IAV infection. We therefore hypothesized that FGF9 would protect the lungs from respiratory virus infection and evaluated IAV pathogenesis in mice that overexpress FGF9 in club cells in the conducting airway epithelium (FGF9-OE mice). However, we found that FGF9-OE mice were highly susceptible to IAV and Sendai virus infection compared to control mice. FGF9-OE mice displayed elevated and persistent viral loads, increased expression of cytokines and chemokines, and increased numbers of infiltrating immune cells as early as 1 day post-infection (dpi). Gene expression analysis showed an elevated type I interferon (IFN) signature in the conducting airway epithelium and analysis of IAV tropism uncovered a dramatic shift in infection from the conducting airway epithelium to the alveolar epithelium in FGF9-OE lungs. These results demonstrate that FGF9 signaling primes the conducting airway epithelium to rapidly induce a localized, protective IFN and proinflammatory cytokine response during viral infection. Although this response protects the airway epithelial cells from IAV infection, it allows for early and enhanced infection of the alveolar epithelium, ultimately leading to increased morbidity and mortality. Our study illuminates a novel role for FGF9 in regulating respiratory virus infection and pathogenesis. Author SummaryInfluenza viruses are respiratory viruses that cause significant morbidity and mortality worldwide. In the lungs, influenza A virus primarily infects epithelial cells that line the conducting airways and alveoli. Fibroblast growth factor-9 (FGF9) is a growth factor that has been shown to have antiviral activity and is upregulated during early IAV infection in asymptomatic patients, leading us to hypothesize that FGF9 would protect the lung epithelium from IAV infection. However, mice that express and secrete FGF9 from club cells in the conducting airway had more severe respiratory virus infection and a hyperactive inflammatory immune response as early as 1 day post-infection. Analysis of the FGF9-expressing airway epithelial cells found an elevated antiviral and inflammatory interferon signature, which protected these cells from severe IAV infection. However, heightened infection of alveolar cells resulted in excessive inflammation in the alveoli, resulting in more severe disease and death. Our study identifies a novel antiviral and inflammatory role for FGFs in the lung airway epithelium and confirms that early and robust IAV infection of alveolar cells results in more severe disease.

immunology↗