title: Pharmacologic activation of the innate immune system to prevent respiratory viral infections.
abstract: Drugs that can rapidly inhibit respiratory infection from influenza or other respiratory pathogens are needed. One approach is to engage primary innate immune defenses against viral infection, such as activating the IFN pathway. In this study, we report that a small, cell-permeable compound called 5,6-di-methylxanthenone-4-acetic acid (DMXAA) can induce protection against vesicular stomatitis virus in vitro and H1N1 influenza A virus in vitro and in vivo through innate immune activation. Using the mouse C10 bronchial epithelial cell line and primary cultures of nasal epithelial cells, we demonstrate DMXAA activates the IFN regulatory factor-3 pathway leading to production of IFN-β and subsequent high-level induction of IFN-β-dependent proteins, such as myxovirus resistance 1 (Mx1) and 2',5'-oligoadenylate synthetase 1 (OAS1). Mice treated with DMXAA intranasally elevate mRNA/protein expression of Mx1 and OAS1 in the nasal mucosa, trachea, and lung. When challenged intranasally with a lethal dose of H1N1 influenza A virus, DMXAA reduced viral titers in the lungs and protected 80% of mice from death, even when given at 24 hours before infection. These data show that agents, like DMXAA, that can directly activate innate immune pathways, such as the IFN regulatory factor-3/IFN-β system, in respiratory epithelial cells can be used to protect from influenza pneumonia and potentially in other respiratory viral infections. Development of this approach in humans could be valuable for protecting health care professionals and "first responders" in the early stages of viral pandemics or bioterror attacks.
authors.affiliation: Thoracic Oncology Research Laboratory, 1015F ARC, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318, USA.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Liang-Chuan S
authors.initials: LC
authors.lastname: Wang
authors.forename: Zvi G
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: Guang-Shing
authors.initials: GS
authors.lastname: Cheng
authors.forename: Bei
authors.initials: B
authors.lastname: Chen
authors.forename: Nilam S
authors.initials: NS
authors.lastname: Mangalmurti
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Saloura
authors.forename: Zaifang
authors.initials: Z
authors.lastname: Yu
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Krystyna
authors.initials: K
authors.lastname: Mozdzanowska
authors.forename: Edmund
authors.initials: E
authors.lastname: Moon
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: James L
authors.initials: JL
authors.lastname: Kreindler
authors.forename: Noam A
authors.initials: NA
authors.lastname: Cohen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
authors.forename: Jan
authors.initials: J
authors.lastname: Erikson
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001980:Bronchi / Q000821:virology; D004847:Epithelial Cells / Q000821:virology; D005260:Female; D006801:Humans; D007107:Immune System; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007251:Influenza, Human / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012141:Respiratory Tract Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology*; D014777:Virus Diseases / Q000276:immunology / Q000517:prevention & control*; D044004:Xanthones / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan