Pharmacologic activation of the innate immune system to prevent respiratory viral infections

Guanjun Cheng, Liang Chuan S. Wang*, Zvi G. Fridlender, Guang Shing Cheng, Bei Chen, Nilam S. Mangalmurti, Vassiliki Saloura, Zaifang Yu, Veena Kapoor, Krystyna Mozdzanowska, Edmund Moon, Jing Sun, James L. Kreindler, Noam A. Cohen, Andrew J. Caton, Jan Erikson, Steven M. Albelda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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 compoundcalled 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 immuneactivation. Using themouseC10bronchial 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 IFNβ-dependent proteins, such as myxovirus resistance 1 (Mx1) and 2′,5′-oligoadenylate synthetase 1(OAS1).Micetreated withDMXAA 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 protected80%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-′ 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.

Original languageAmerican English
Pages (from-to)480-488
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number3
StatePublished - 1 Sep 2011
Externally publishedYes


  • Bronchial epithelium
  • Influenza
  • Innate immunity
  • Interferon
  • Pneumonia


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