Short-Term Heat Shock Affects Host–Virus Interaction in Mice Infected with Highly Pathogenic Avian Influenza Virus H5N1

Abstract

Highly pathogenic avian influenza virus (HPAIV) H5N1 is a highly contagious virus that can cause acute respiratory infections and high human fatality ratio due to excessive inflammatory response. Short-term heat shock, as a stressful condition, could induce the expression of heat shock proteins that function as molecular chaperones to protect cells against multiple stresses. However, the protective effect of short-term heat shock in influenza infection is far from being understood. In this study, mice were treated at 39°C for 4 h before being infected with HPAIV H5N1. Interestingly, short-term heat shock significantly increased the levels of HSP70 and pro-inflammatory cytokines IL-6, TNF-α, IFN-β, and IFN-γ in the lung tissues of mice. Following HPAIV H5N1 infection, short-term heat shock alleviated immunopathology and viral replication in lung tissue and repressed the weight loss and increased the survival rate of H5N1-infected mice. Our data reported that short-term heat shock provided beneficial anti-HPAIV H5N1 properties in mice model, which offers an alternative strategy for non-drug prevention for influenza infection.

Current and Future Developments in the Treatment of Virus-Induced Hypercytokinemia

“…The heat shock-treated mice were found to have reduced lung pathological damages, reduced body weight loss and virus replication in the lung tissues which was found to correlate with an increased expression of HSP70 in the lungs of the heat shock-treated group when compared with the control [29]. Intriguingly, the expression of proinflammatory cytokines IL-6, IFN-β and IFN-α were significantly reduced at day 6 and a reduction in the presence of TNF-α level was also noted at day 1 post-infection within the lungs of mice which received the heat shock treatment when compared with the untreated control group [29]. The beneficial effects of heat shock treatment against HPAI in this study was hypothesized to be correlated with the increased expression and protective effects of HSP70 which was also associated with transient downregu-lation of the over-expressions of pro-inflammatory c ytokines in the lungs.…”

“…However, when the heat shock-treated mice were challenged with a lethal dose of HPAI virus, 57% of the heat shocktreated mice survived the virus challenge at day 14 post-infection compared with 0% survival in the untreated control group [29]. The heat shock-treated mice were found to have reduced lung pathological damages, reduced body weight loss and virus replication in the lung tissues which was found to correlate with an increased expression of HSP70 in the lungs of the heat shock-treated group when compared with the control [29]. Intriguingly, the expression of proinflammatory cytokines IL-6, IFN-β and IFN-α were significantly reduced at day 6 and a reduction in the presence of TNF-α level was also noted at day 1 post-infection within the lungs of mice which received the heat shock treatment when compared with the untreated control group [29].…”

“…HSPs also play an important role in regulating innate and adaptive immune responses, including activating monocytes, dendritic cells, macrophages and inducing production of pro-inflammatory cytokines (review, [28]). Short-term heat shock (39°C for 4 h) treatment of mice resulted in significant increased levels of HSP70 (a key member of the HSP protein family known to play in a role in antiviral immunity), and in the levels of pro-inflammatory cytokines IL-6, TNF-α, IFN-β and IFN-γ [29]. However, when the heat shock-treated mice were challenged with a lethal dose of HPAI virus, 57% of the heat shocktreated mice survived the virus challenge at day 14 post-infection compared with 0% survival in the untreated control group [29].…”

“…Short-term heat shock (39°C for 4 h) treatment of mice resulted in significant increased levels of HSP70 (a key member of the HSP protein family known to play in a role in antiviral immunity), and in the levels of pro-inflammatory cytokines IL-6, TNF-α, IFN-β and IFN-γ [29]. However, when the heat shock-treated mice were challenged with a lethal dose of HPAI virus, 57% of the heat shocktreated mice survived the virus challenge at day 14 post-infection compared with 0% survival in the untreated control group [29]. The heat shock-treated mice were found to have reduced lung pathological damages, reduced body weight loss and virus replication in the lung tissues which was found to correlate with an increased expression of HSP70 in the lungs of the heat shock-treated group when compared with the control [29].…”

Can the hyperthermia‐mediated heat shock factor/heat shock protein 70 pathway dampen the cytokine storm during SARS‐CoV‐2 infection?

“…Another mechanism proposed involves the capacity of HSP70 to inhibit LPS-induced NF-κB activation by interacting directly with tumour necrosis factor receptor-associated factor 6 (TRAF6), a member of the TLRs and interleukin 1 receptor, type I transduction pathways (Chen et al, 2006). In a viral-infection context, heat shock was shown to be able to dampen IL-6, TNFα, IFNβ and IFNγ production in H5N1-infected mice (Xue et al, 2016). HSF-1 is also able to interact with CCAAT enhancer binding protein (C/EBPβ) to repress the transcription of IL-1B in human monocytes treated with LPS (Xie, Chen, Stevenson, Auron, & Calderwood, 2002).…”