Abstract
ABSTRACTHost-derived “danger-associated molecular patterns” (DAMPs) contribute to innate immune responses and serve as markers of disease progression and severity for inflammatory and infectious diseases. There is accumulating evidence that generation of DAMPs such as oxidized phospholipids and high-mobility-group box 1 (HMGB1) during influenza virus infection leads to acute lung injury (ALI). Treatment of influenza virus-infected mice and cotton rats with the Toll-like receptor 4 (TLR4) antagonist Eritoran blocked DAMP accumulation and ameliorated influenza virus-induced ALI. However, changes in systemic HMGB1 kinetics during the course of influenza virus infection in animal models and humans have yet to establish an association of HMGB1 release with influenza virus infection. To this end, we used the cotton rat model that is permissive to nonadapted strains of influenza A and B viruses, respiratory syncytial virus (RSV), and human rhinoviruses (HRVs). Serum HMGB1 levels were measured by an enzyme-linked immunosorbent assay (ELISA) prior to infection until day 14 or 18 post-infection. Infection with either influenza A or B virus resulted in a robust increase in serum HMGB1 levels that decreased by days 14 to 18. Inoculation with the live attenuated vaccine FluMist resulted in HMGB1 levels that were significantly lower than those with infection with live influenza viruses. RSV and HRVs showed profiles of serum HMGB1 induction that were consistent with their replication and degree of lung pathology in cotton rats. We further showed that therapeutic treatment with Eritoran of cotton rats infected with influenza B virus significantly blunted serum HMGB1 levels and improved lung pathology, without inhibiting virus replication. These findings support the use of drugs that block HMGB1 to combat influenza virus-induced ALI.
Highlights
Host-derived “danger-associated molecular patterns” (DAMPs) contribute to innate immune responses and serve as markers of disease progression and severity for inflammatory and infectious diseases
Serum high-mobility-group box 1 (HMGB1) levels increase upon influenza B/Wisconsin virus infection of cotton rats
In response to live influenza B virus, serum HMGB1 levels gradually increased over days 2 to 4 p.i., reached peak concentrations at days 6 to 8 p.i. (~100 ng/ml), and declined over days 10 to 14 p.i., almost reaching background levels by day 18 p.i
Summary
Host-derived “danger-associated molecular patterns” (DAMPs) contribute to innate immune responses and serve as markers of disease progression and severity for inflammatory and infectious diseases. We further showed that therapeutic treatment with Eritoran of cotton rats infected with influenza B virus significantly blunted serum HMGB1 levels and improved lung pathology, without inhibiting virus replication. These findings support the use of drugs that block HMGB1 to combat influenza virus-induced ALI. Towards development of a new therapeutic modality, we show that blocking serum HMGB1 levels by Eritoran improves lung pathology in influenza B virus-infected cotton rats. A new and very different influenza A virus to which humans have no prior immunity may appear due to “antigenic shift” caused by recombination of the eightsegment genome of human influenza virus with the genomes of influenza viruses of swine or avian origin Such strains may result in catastrophic pandemics, such as the 1918 “Spanish flu” [3]. It would be highly beneficial to develop alternative therapeutic adjuncts to mitigate influenza virus-induced disease
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