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.

Effects of Type 1 Diabetes-Associated IFIH1 Polymorphisms on MDA5 Function and Expression

“…In line with this observation, ectopic expression of the Thr 946 allele in K562 cells resulted in a relative decrease in IFNα, TNFα, and Casp8 expression and concomitant increase in MX1, MAVS, and MAPK8 [52]. As IFNβ is essential for expression of MX1, these results suggest an IFNβ-mediated IFN response [58,59]. Furthermore, these studies support the trend of reduced IFNα reported by Polychronakos et al [56].…”

Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response

“…Nonetheless, modulation of host pathways for enhancement of the innate immune response through chemicals could be a viable strategy for the development of antiviral therapy, and has been of growing interest recently [25,26]. It can be expected that such immunomodulators are effective against a range of different viral pathogens through the many facets of the host immune response.…”

5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential

“…Despite showing promise in initial phase II trials for treatment of nonsmall cell lung cancer in combination with the current chemotherapeutic regimen of carboplatin and paclitaxel (8,9), DMXAA did not show efficacy in the most recent phase III clinical trial (10). However, induction of IFN-␤ also allows DMXAA to act as an antiviral agent during in vitro infection of multiple cell types with a variety of influenza strains (including a Tamiflu-resistant strain) and during in vivo infection of mice with mouse-adapted influenza A virus (11,12). Combined with its use as a tool to study signaling pathways activated by intracellular pathogens, understanding the mechanism of DMXAA-mediated up-regulation of IFN-␤ would benefit multiple fields of study.…”