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* Pulmonary and Critical Care Medicine, Department of Medicine,
Department of Pediatrics, and
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110
The epithelial surface is often proposed to actively participate in host defense, but evidence that this is the case remains circumstantial. Similarly, respiratory paramyxoviral infections are a leading cause of serious respiratory disease, but the basis for host defense against severe illness is uncertain. Here we use a common mouse paramyxovirus (Sendai virus) to show that a prominent early event in respiratory paramyxoviral infection is activation of the IFN-signaling protein Stat1 in airway epithelial cells. Furthermore, Stat1–/– mice developed illness that resembled severe paramyxoviral respiratory infection in humans and was characterized by increased viral replication and neutrophilic inflammation in concert with overproduction of TNF-
and neutrophil chemokine CXCL2. Poor control of viral replication as well as TNF- and CXCL2 overproduction were both mimicked by infection of Stat1–/– airway epithelial cells in culture. TNF- drives the CXCL2 response, because it can be reversed by TNF- blockade in vitro and in vivo. These findings pointed to an epithelial defect in Stat1–/– mice. Indeed, we next demonstrated that Stat1–/– mice that were reconstituted with wild-type bone marrow were still susceptible to infection with Sendai virus, whereas wild-type mice that received Stat1–/– bone marrow retained resistance to infection. The susceptible epithelial Stat1–/– chimeric mice also exhibited increased viral replication as well as excessive neutrophils, CXCL2, and TNF- in the airspace. These findings provide some of the most definitive evidence to date for the critical role of barrier epithelial cells in innate immunity to common pathogens, particularly in controlling viral replication.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases), the Martin Schaeffer Fund, and the Alan A. and Edith L. Wolff Charitable Trust (to M.J.H.), by a Parker B. Francis Foundation Pulmonary Research Fellowship (to L.P.S.), and a Pediatric Scientist Development Award from the National Institute of Child Health and Human Development (to A.G.W.).
2 Address correspondence and reprint requests to Dr. M. J. Holtzman, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: holtzmanm{at}wustl.edu
3 Abbreviations used in this paper: SeV, Sendai virus; BAL, bronchoalveolar lavage; MOI, multiplicity of infection; mTEC, mouse tracheal epithelial cell; PI, postinoculation; RSV, respiratory syncytial virus; SeV-UV, UV-inactivated SeV.
4 The on-line version of this article contains supplemental material.
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