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Systemic Release of High Mobility Group Box 1 Protein during Severe Murine Influenza¹

School of Biochemistry and Molecular Biology, Australian National University, Canberra, Australian Capital Territory, Australia

Hypercytokinemia is gaining recognition as the mechanism of fatality from influenza. No work to date has addressed the role of high mobility group box 1 protein (HMGB1) in influenza, the parallel being that in other severe proinflammatory cytokine syndromes (e.g., sepsis and malaria) levels of circulating HMGB1 are elevated and may correlate with death. Using a commercially available ELISA for HMGB1, we found that HMGB1 was not increased in the plasma of influenza virus-infected mice (A/Japan/305/57) on day 7 post infection, about the time of peak mortality, and peak levels of HMGB1 in the plasma did not occur until relatively late in infection, on day 9 post infection. In keeping with the late peak of HMGB1 being unassociated with mortality, administration of ethyl pyruvate, which inhibits active secretion but not passive release of HMGB1, to influenza virus-infected mice, did not affect their survival. Further work is required to determine whether influenza virus infection induces passive release of HMGB1, and whether HMGB1 neutralization with a specific Ab would improve survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Health and Medical Research Council of Australia (410222).

² L.M.A. and A.C.B. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Lisa Alleva, School of Biochemistry and Molecular Biology, Building 41 Linnaeus Way, Australian National University, Canberra, Australian Capital Territory 0200, Australia. E-mail address: lisa.alleva{at}anu.edu.au

⁴ Abbreviations used in this paper: HMGB1, high mobility group box 1 protein; p.i., post infection; HAU, hemagglutination units.