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Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses
Published on: January 20, 2017
Novel strategies for targeting innate immune responses to influenza
K A Shirey1, W Lai1, M C Patel1,2
1Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, USA.
Abstract:
We previously reported that TLR4(-/-) mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist Eritoran blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post infection. Herein we extend these findings: anti-TLR4- or -TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h before PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4(-/-) mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks high-mobility group B1 (HMGB1)-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI; (iii) interleukin (IL)-1β contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the antiviral drug oseltamivir were administered starting 4 days post infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection.
Insights
Toll-like receptor 4 (TLR4) antagonists like Eritoran offer protection against lethal influenza by blocking high-mobility group B1 (HMGB1) signaling and reducing lung injury. This host-targeted approach shows promise for influenza treatment.
Area of Science:
- Immunology
- Virology
- Pharmacology
Background:
- Toll-like receptor 4 (TLR4) signaling plays a critical role in influenza-induced lethality.
- Previous studies showed TLR4 knockout mice are resistant to lethal influenza, and TLR4 antagonists can protect against severe outcomes.
Purpose of the Study:
- To investigate the protective mechanisms of TLR4 antagonists against lethal influenza.
- To explore the role of high-mobility group B1 (HMGB1) and interleukin-1 beta (IL-1β) in influenza pathogenesis and potential therapeutic targets.
Main Methods:
- Administration of TLR4 antagonist Eritoran, anti-TLR4/TLR2 IgG, HMGB1 inhibitor, and IL-1 receptor antagonist (IL-1Ra) in mouse models of influenza A (PR8 strain).
- Assessment of lethality, acute lung injury (ALI), pulmonary edema, and adaptive immune responses.
- In vitro studies on TLR4-dependent signaling.
Main Results:
- Eritoran and anti-TLR4/TLR2 IgG therapy conferred significant protection against lethal PR8 influenza.
- Eritoran blocked HMGB1-mediated TLR4 signaling and reduced lung edema, but failed to protect when given prophylactically.
- IL-1β contributes to influenza lethality, and IL-1Ra provided partial protection.
- Synergistic protection was observed with combined Eritoran and oseltamivir treatment.
- Eritoran treatment did not impair adaptive immunity to subsequent influenza challenge.
Conclusions:
- Host-targeted therapies, including TLR4 antagonists and HMGB1 inhibition, show potential for treating severe influenza.
- Blocking HMGB1-mediated signaling and IL-1β are viable therapeutic strategies.
- Combination therapy with antivirals may enhance treatment efficacy.
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