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Subversion of Pulmonary Dendritic Cell Function by Paramyxovirus Infections¹

Antonieta Guerrero-Plata^2,*, Deepthi Kolli^*, Chao Hong^*, Antonella Casola^*,, and Roberto P. Garofalo^2,*,,

^* Department of Pediatrics, Department of Microbiology and Immunology, and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555

Lower respiratory tract infections caused by the paramyxoviruses human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are characterized by short-lasting virus-specific immunity and often long-term airway morbidity, both of which may be the result of alterations in the Ag-presenting function of the lung which follow these infections. In this study, we investigated whether hMPV and RSV experimental infections alter the phenotype and function of dendritic cell (DC) subsets that are recruited to the lung. Characterization of lung DC trafficking demonstrated a differential recruitment of plasmacytoid DC (pDC), conventional DC (cDC), and IFN-producing killer DC to the lung and draining lymph nodes after hMPV and RSV infection. In vitro infection of lung DC indicated that in pDC, production of IFN-, TNF-, and CCL5 was induced only by hMPV, whereas CCL3 and CCL4 were induced by both viruses. In cDC, a similar repertoire of cytokines was induced by hMPV and RSV, except for IFN-β, which was not induced by RSV. The function of lung pDC was altered following hMPV or RSV infection in vivo, as we demonstrated a reduced capacity of lung pDC to produce IFN- as well as other cytokines including IL-6, TNF-, CCL2, CCL3, and CCL4 in response to TLR9 stimulation. Moreover, we observed an impaired capacity of cDC from infected mice to present Ag to CD4⁺ T cells, an effect that lasted beyond the acute phase of infection. Our findings suggest that acute paramyxovirus infections can alter the long-term immune function of pulmonary DC.

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 National Institutes of Health Grants P01 AI062885 and N01 AI30039 (to R.P.G.), an Unrestricted Research Grant from the American Thoracic Society, and a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (to A.G.-P.).

² Address correspondence and reprint requests to Dr. Antonieta Guerrero-Plata or Dr. Roberto P. Garofalo, Department of Pediatrics, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0366. E-mail addresses: maaguerr{at}utmb.edu or rpgarofa{at}utmb.edu

³ Abbreviations used in this paper: hMPV, human metapneumovirus; RSV, respiratory syncytial virus; DC, dendritic cell; IKDC, IFN-producing killer DC; pDC, plasmacytoid DC; cDC, conventional DC; ODN, oligodeoxynucleotide; LN, lymph node; MOI, multiplicity of infection; PD-L, programmed death ligand; MHC-II, MHC class II.