Potential role of high-mobility group box 1 protein in the pathogenesis of influenza H5N1 virus infection

Abstract

Summary. -During influenza A virus (IAV) (H5N1) infection, the levels of inflammatory cytokines are markedly elevated in the lungs of infected hosts. One of them, high-mobility group box 1 protein (HMGB1) functions in regulation of cellular transcription and activation of proinflammatory responses, but little is known about its role in viral infection. In this study, we attempted to address this question. Using an IAV (H5N1) -mouse model, lung tissues were analyzed for virus titer, expression of HMGB1 and other inflammatory cytokines and histopathological changes. Moreover, the effect of administration of HMGB1-specific antibody to the infected mice on these parameters was investigated. The results showed that the HMGB1 expression was induced on days 3-7 post infection (p.i.) and primarily localized to epithelial cells of alveoli and bronchioles. The HMGB1-specific antibody reduced the levels of inflammatory cytokines and chemokines and the survival rate, but did not influence the virus titer. Summing up, these data suggest that HMGB1 contributes to the pathogenesis of IAV (H5N1) infection in mice by inducing extensive inflammatory responses and severe pneumonia. Keywords: HMGB1; influenza A virus (H5N1); pathogenesis * Corresponding authors. E-mail: gywtext@yahoo.com.cn, xia_xzh@ yahoo.com.cn; phone: +86-431-86985516, +86-431-86985517. Abbreviations: HMGB1 = high-mobility group box 1; IAV = influenza A virus; IFN = interferon; IL-1β = interleukin 1β; IL-6 = interleukin 6; IP-10 = IFN-inducible protein 10; p.i. = post infection; RANTES = regulated upon activation, normal T-cell expressed and secreted protein; TNF-α = tumor necrosis factor α

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

“…Although this hypothesis requires further investigation, blocking HMGB1 could be an approach that is readily translated to the clinic given that anti-HMGB1 treatments have already been approved for clinical trials to block systemic inflammation (Ulloa and Messmer, 2006). Interestingly, several of the viruses and bacteria that have been implicated in the pathogenesis of asthma are also known to induce HMGB1 (Moisy et al, 2012; Hou et al, 2014; Wang et al, 2004, 1999). Indeed, our preliminary data suggest that later life exposure to either influenza A virus or lipopolysaccharide (known HMGB1 stimuli) (Nosaka et al, 2015; Gardella et al, 2002) are able to induce at least some features of airway remodelling in RAGE deficient mice that were infected with PVM in early life (data not shown).…”

Porcine epidemic diarrhea virus nucleoprotein contributes to HMGB1 transcription and release by interacting with C/EBP-β

“…The HMGB1 expression is induced in mice on days 3-7 post infection. The HMGB1-specific antibody can reduce the levels of inflammatory cytokines and chemokines and enhance the survival rate, but the virus titer is not affected by HMGB1 antibody treatment [51]. It was proposed that virus-mediated cytolysis after initial acute coronavirus infection of alveolar endothelial cells or macrophages results in HMGB1 release from the damaged cells.…”

Anti-high mobility group box-1 monoclonal antibody treatment provides protection against influenza A virus (H1N1)-induced pneumonia in mice

“…That is, the involvement of inflammatory mediators in the pathogenesis of influenza has been recognized as a major issue [ 31 ]. After HMGB1 was first shown to have an additional function as a late mediator of endotoxin lethality [ 14 ], it has since been revealed as a protein with inflammatory cytokine activity in the pathogenesis of influenza [ 32 – 34 ], as well as in many other inflammatory diseases. Recently, HMGB1 has attracted the attention of many researchers as a therapeutic target for the treatment of various diseases [ 35 ].…”