Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus
Caiqi Zhao, … , Paul H. Lerou, Xingbin Ai
Caiqi Zhao, … , Paul H. Lerou, Xingbin Ai
Published November 1, 2024
Citation Information: J Clin Invest. 2024;134(21):e183978. https://doi.org/10.1172/JCI183978.
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Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus

Abstract

Respiratory syncytial virus (RSV) selectively targets ciliated cells in human bronchial epithelium and can cause bronchiolitis and pneumonia, mostly in infants. To identify molecular targets of intervention during RSV infection in infants, we investigated how age regulates RSV interaction with the bronchial epithelium barrier. Employing precision-cut lung slices and air-liquid interface cultures generated from infant and adult human donors, we found robust RSV virus spread and extensive apoptotic cell death only in infant bronchial epithelium. In contrast, adult bronchial epithelium showed no barrier damage and limited RSV infection. Single nuclear RNA-Seq revealed age-related insufficiency of an antiapoptotic STAT3 activation response to RSV infection in infant ciliated cells, which was exploited to facilitate virus spread via the extruded apoptotic ciliated cells carrying RSV. Activation of STAT3 and blockade of apoptosis rendered protection against severe RSV infection in infant bronchial epithelium. Lastly, apoptotic inhibitor treatment of a neonatal mouse model of RSV infection mitigated infection and inflammation in the lung. Taken together, our findings identify a STAT3-mediated antiapoptosis pathway as a target to battle severe RSV disease in infants.

Authors

Caiqi Zhao, Yan Bai, Wei Wang, Gaurang M. Amonkar, Hongmei Mou, Judith Olejnik, Adam J. Hume, Elke Mühlberger, Nicholas W. Lukacs, Rachel Fearns, Paul H. Lerou, Xingbin Ai

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Figure 10

Blockade of apoptosis ameliorates RSV infection and lung inflammation in neonatal mice.

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Blockade of apoptosis ameliorates RSV infection and lung inflammation in...
(A) Schematic of RSV A2-line19F infection with/without Z-VAD-FMK treatment in neonatal BALB/c mice. Neonatal mice were intranasally given with 1 × 106 RSV in 20 μL of Z-VAD-FMK (0.3 mM) or solvent (3% DMSO). The trachea and lung samples were collected at 3 dpi. (B) Representative images of RSV (red) and AceTUB (green) staining in mouse trachea. Blue color is nucleus staining and the overlay of red and green shows as yellow color. (C) Representative images of RSV (red) and c-Casp-3 (green) staining in control and Z-VAD-FMK–treated mouse trachea. White arrows mark infected cells. (D) Relative abundance of RSV + cells and RSV+c-Casp-3+ cells in mouse trachea. (E) Representative image of periodic acid–Schiff (PAS) staining in trachea sections of neonatal mice. Black arrows mark positive staining. (F) Representative images of RSV (red), AceTUB (green), and p-STAT3 (red) staining using 2 adjacent trachea sections (4μm apart) of neonatal mice. Blue color is nucleus staining and the overlay of red and green shows as yellow color. Yellow arrows mark 2 p-STAT3+ cells in the parenchyma that are not infected. (G–P) The relative levels of RSV L gene (G), Muc5ac (H), Cxcl2 (I), Cxcl10 (J), Cxcl11 (K), Tnf (L), Il6 (M), Ifna (N), Ifnb1 (O), and Ifng (P) gene expression in neonatal lung at 3 dpi by RT-qPCR. Dotted lines mark basement membrane. Each dot represents 1 mouse. *P < 0.05, **P < 0.01, and ***P < 0.001 by Student’s t test. Scale bar: 50 μm.