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SEVERE INFLUENZA INFECTION IS ASSOCIATED WITH INFLAMMATORY PROGRAMMED CELL DEATH IN INFECTED MACROPHAGES
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Abstract
Introduction: Influenza A virus (IAV) is one of the leading causes of respiratory tract
infections in humans, representing a major public health concern. The various
types of cell death have a crucial role in IAV pathogenesis because this virus may
trigger both apoptosis and necroptosis in airway epithelial cells in parallel.
Macrophages play an important role in the clearance of virus particles, priming
the adaptive immune response in influenza. However, the contribution of
macrophage death to pathogenesis of IAV infection remains unclear.
Methods: In this work, we investigated IAV-induced macrophage death, along with
potential therapeutic intervention. We conducted in vitro and in vivo experiments
to evaluate the mechanism and the contribution of macrophages death to the
inflammatory response induced by IAV infection.
Results: We found that IAV or its surface glycoprotein hemagglutinin (HA) triggers
inflammatory programmed cell death in human and murine macrophages in a
Toll-like receptor-4 (TLR4)- and TNF-dependent manner. Anti-TNF treatment in
vivo with the clinically approved drug etanercept prevented the engagement of the
necroptotic loop and mouse mortality. Etanercept impaired the IAV-induced
proinflammatory cytokine storm and lung injury.
Conclusion: In summary, we demonstrated a positive feedback loop of events that
led to necroptosis and exacerbated inflammation in IAV-infected macrophages.
Our results highlight an additional mechanism involved in severe influenza that
could be attenuated with clinically available therapies.
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