Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury.

Kari Ann Shirey,Jorge C G Blanco,Stefanie N Vogel

doi:10.3389/fimmu.2021.705080

Kari Ann Shirey, Jorge C G Blanco + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2021.705080

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Abstract

Respiratory viral infections have been a long-standing global burden ranging from seasonal recurrences to the unexpected pandemics. The yearly hospitalizations from seasonal viruses such as influenza can fluctuate greatly depending on the circulating strain(s) and the congruency with the predicted strains used for the yearly vaccine formulation, which often are not predicted accurately. While antiviral agents are available against influenza, efficacy is limited due to a temporal disconnect between the time of infection and symptom development and viral resistance. Uncontrolled, influenza infections can lead to a severe inflammatory response initiated by pathogen-associated molecular patterns (PAMPs) or host-derived danger-associated molecular patterns (DAMPs) that ultimately signal through pattern recognition receptors (PRRs). Overall, these pathogen-host interactions result in a local cytokine storm leading to acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS) with concomitant systemic involvement and more severe, life threatening consequences. In addition to traditional antiviral treatments, blocking the host’s innate immune response may provide a more viable approach to combat these infectious pathogens. The SARS-CoV-2 pandemic illustrates a critical need for novel treatments to counteract the ALI and ARDS that has caused the deaths of millions worldwide. This review will examine how antagonizing TLR4 signaling has been effective experimentally in ameliorating ALI and lethal infection in challenge models triggered not only by influenza, but also by other ALI-inducing viruses.

Highlights

Many pathogens mutate rapidly, leading to anti-microbial resistance or altered expression of immunogenic epitopes such that extant vaccines or therapeutic drugs are rendered ineffective
We have all become too familiar with COVID-19 pandemic that has led to acute lung injury (ALI), as well as the more severe acute respiratory distress syndrome (ARDS) and the deaths of millions worldwide
In support of the observation that Toll-like receptor 4 (TLR4)-/- mice are extremely refractory to influenza infection [20, 24], other studies have subsequently shown that many TLR4 antagonists, that act by a variety of distinct mechanisms to prevent signaling all block influenza-induced lethality

Summary

Introduction

Many pathogens mutate rapidly, leading to anti-microbial resistance or altered expression of immunogenic epitopes such that extant vaccines or therapeutic drugs are rendered ineffective. Both curcumin and its analogs have been shown to block TLR4 signaling during LPS-induced sepsis and ALI through various mechanisms including binding MD-2 and inhibiting NF-kB or ERK activation [58,59,60].

Results

Conclusion