In humans, Toll-like receptors (TLRs) are a closely related family of 10 transmembrane PRRs that sense unique microbial chemistries or PAMPs and/or host-derived DAMPs ( 5, 6). These molecules are collectively referred to as “danger-associated molecular patterns” (DAMPs) ( 1), and activate identical PRR signaling pathways, e.g., HMGB1 is a chromatin-associated protein that, when actively secreted or released from dying cells ( 3), engages TLR4 through its co-receptor, MD-2, and elicits a pro-inflammatory response similar to that of LPS ( 4). Also, as part of this rapid response, host-derived molecules are often released during cellular necrosis or are secreted upon cellular stress. Such “pattern recognition receptors” (PRR) ( 1) are expressed on cells of the innate immune system and their activation initiates intracellular signaling and transcriptional programs that lead to a rapid and strong primary response against the pathogen, e.g., Gram-negative lipopolysaccharide (LPS) interacts with Toll-like receptor 4 (TLR4) leading to the induction of thousands of genes, many of which are proinflammatory ( 2). The ability of the host to recognize and respond to immunologic “danger” is the result of the exposure of the host to a pathogen’s unique components known as “pathogen-associated molecular patterns” (PAMP) that are readily detected by host surveillance receptors. 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. 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.
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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. In addition to traditional antiviral treatments, blocking the host’s innate immune response may provide a more viable approach to combat these infectious pathogens. 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. 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). 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.
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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. Respiratory viral infections have been a long-standing global burden ranging from seasonal recurrences to the unexpected pandemics.