JVI Accepts, published online ahead of print on 12 November 2008

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J. Virol. doi:10.1128/JVI.01792-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV)-Induced Lung Epithelial Cytokines Exacerbate SARS Pathogenesis by Modulating Intrinsic Functions of Monocyte-Derived Macrophages and Dendritic Cells

Tomoki Yoshikawa, Terence Hill, Clarence J. Peters, and Chien-Te K. Tseng^*

Departments of Microbiology and Immunology, Pathology, and the Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas 77555

^* To whom correspondence should be addressed. Email: sktseng{at}utmb.edu.

Severe acute respiratory syndrome (SARS), caused by a novel coronavirus (CoV), is a highly communicable disease with the lungs as the major pathological target. Although SARS likely stems from over-exuberant host inflammatory responses, the exact mechanism leading to the detrimental outcome in patients remains unknown. Pulmonary macrophages (M), airway epithelium, and dendritic cells (DC) are key cellular elements of the host innate defenses against respiratory infections. While pulmonary M are situated at the luminal epithelial surface, DC reside abundantly underneath the epithelium. Such strategic locations of these cells within the airways make it relevant to investigate their likely impact on SARS pathogenesis subsequent to their interaction with infected lung epithelial cells. To study this we established highly polarized human lung epithelial Calu-3 cells by using the Transwell^TM culture system. Here we report that supernatants harvested from the apical and basolateral domains of infected Calu-3 cells are potent in modulating the intrinsic functions of M and DC, respectively. They prompted the production of cytokines by both M and DC, and selectively induced CD40 and CD86 expression only on DC. However, they compromised the DC's and M's abilities in priming naïve T cells and phagocytosis, respectively. We also identified IL-6 and IL-8 as key SARS-CoV-induced epithelial cytokines capable of inhibiting DC's T cell-priming ability. Taken together, our results provide insights into the molecular and cellular basis of the host antiviral innate immunity within the lungs that eventually lead to exacerbated inflammatory cascades and severe tissue damage in SARS patients.

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