Inhibiting retinoic acid signaling in dendritic cells suppresses respiratory syncytial virus infection through enhanced antiviral immunity
Mohammad Farazuddin,
Grant Acker,
Joseph Zourob,
Jessica J. O’Konek,
Pamela T. Wong,
Susan Morris,
Andrew J. Rasky,
Chang H. Kim,
Nicholas W. Lukacs,
James R. Baker, Jr.
Affiliations
Mohammad Farazuddin
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, USA; Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA
Grant Acker
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, USA; Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA
Joseph Zourob
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, USA; Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA
Jessica J. O’Konek
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, USA; Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA
Pamela T. Wong
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, USA; Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA
Susan Morris
Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Andrew J. Rasky
Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Chang H. Kim
Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
Nicholas W. Lukacs
Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
James R. Baker, Jr.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI, USA; Mary H. Weiser Food Allergy Center, University of Michigan Medical School, Ann Arbor, MI, USA; Corresponding author
Summary: Retinoic acid (RA), controls the immunoregulatory functions of many immune cells, including dendritic cells (DCs), and is important for mucosal immunity. In DCs, RA regulates the expression of pattern recognition receptors and stimulates interferon production. Here, we investigated the role of RA in DCs in mounting immunity to respiratory syncytial virus (RSV). To abolish RA signaling in DCs, we used mice expressing a dominant negative form of retinoic acid receptor-α (RARα) under the CD11c promoter (CD11c-dnRARα). Paradoxically, upon RSV challenge, these animals had lower viral burden, reduced pathology, and greater Th1 polarized immunity than wild-type (WT) mice. Moreover, CD11c-dnRARα DCs infected with RSV showed enhancement in innate and adaptive immunity genes, while genes associated with viral replication were downregulated. These findings suggest that the absence of RA signaling in DCs enhances innate immunity against RSV infection leading to decreased viral load and reduced pathogenicity.
