Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury

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.

Irisin, Exercise, and COVID-19

“…The second stage of injury, induced by CRS during influenza infections, can be mediated by DAMP-TLR4 dependent activation that results in pulmonary injury (89). We hypothesized that similar events occur during SARS-CoV2 infection, in which DAMP released during the second stage of SARS-CoV2 infection can further damage the lungs (88)(89)(90). Therefore, as irisin reduces TLR4 expression levels, which could decrease patient immune responses to PAMPs and DAMPs, and maybe COVID-19 patient prognosis.…”

Intestinal Microbiota - An Unmissable Bridge to Severe Acute Pancreatitis-Associated Acute Lung Injury

“…Then, the DAMPs could be initiated in the lung tissue that causes a cascade reaction, including the extracellular migration of pro-inflammatory factors such as high mobility group box-1 (HMGB1), heat shock proteins (HSPs), and their bindings to the receptor for advanced glycation end products (RAGE), Toll-like receptor2 (TLR-2), and Toll-like receptor4 (TLR-4) on the surface of AECs. It will create a positive feedback loop that further leads to the upregulation of necrosis, apoptosis, and edema in the lungs ( 90 – 92 ). Elevated HMGB1 levels in lung tissue and bronchoalveolar lavage fluid (BALF) are demonstrated to be positively correlated with the level of pro-inflammatory cytokines using the PALI mice model.…”

Activation of TLR4 by viral glycoproteins: A double-edged sword?

“…However, the mechanisms underlying TLR4 activation by these proteins is still poorly understood. It should be noted that influenza virus infection has also been associated with TLR4 activation, but this has been attributed to the production of DAMPs such as high mobility group box 1 (HMGB1) from infected cells, rather than a viral glycoprotein ( Shirey et al, 2021 ). While it is possible that DAMPs also contribute to TLR4 activation in the context of other viral infections, we have focused this review on the current literature implicating a specific role for viral glycoproteins in activation of TLR4.…”