Induction of high-mobility group Box-1 in vitro and in vivo by respiratory syncytial virus

Abstract

Background Despite decades have passed since its discovery, accurate biomarkers of Respiratory syncytial virus (RSV) disease activity and effective therapeutic strategies are still lacking. The high mobility group box type 1 (HMGB1) protein has been proposed as a possible link between RSV and immune system, but only limited information is currently available to support this hypothesis. Methods Expression of HMGB1 gene and protein were analyzed by quantitative PCR, ELISA, Western blot, immunocytochemistry, and confocal microscopy in immortalized and primary human bronchial epithelial cells, as well as in rat pup lungs. The role of HMGB1 in RSV infection was explored using glycyrrhizin, a selective HMGB1 inhibitor. Results RSV infection strongly induced HMGB1 expression both in vitro and in vivo. Glycyrrhizin dose-dependently inhibited HMGB1 upregulation in both RSV-infected immortalized and primary human bronchial epithelial cells, and this effect was associated with significant reduction of viral replication. Conclusions Our data suggest that HMGB1 expression increases during RSV replication. This seems to play a critical pathogenic role as its selective inhibition virtually modified the infection. These observations provide further insight into the pathophysiology of RSV infection and uncover a potential biomarker and therapeutic target for the most common respiratory infection of infancy.

Cloning, Expression, and Purification of a Pathogenesis-Related Protein from <i>Oenanthe javanica</i> and Its Biological Properties

“…46) Notably, OJPR + macrophages led to overexpression of HMGB1 gene that interacts with nucleosomes, transcription factor, and histones, suggesting that the existence of OJPR within the cell may impart biological potentialityinbothinnateimmunereactionandinflammationmediated pathogenesis as a therapeutic modulator. 47,48) Moreover, marked inhibition of OJPR activity by TLR4 and MAP kinase kinases inhibitor (TAK-242 and PD98059) strongly indicated that OJPR can act as a modulator for TLR4/MyD88 signalcascades.Onthecontrary,OJPRsignificantlyincreased the anti-viral repertoires, including IFNγ, IFNα, OAS1, and Mx1 which are directly associated with anti-viral responses in CD4 + primary T cells. Nonetheless, it remains to be elucidated more about the OJPR under the eukaryote expression system which includes post-transcriptional modification to reachtheirfinalstructurebymolecularchaperones.…”

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

“…The biological implications of this mechanism may be of tremendous importance for the pathogenesis of severe pulmonary inflammation because the high constitutive cell surface RAGE expression. It has been demonstrated in preclinical and clinical studies that severe respiratory infections including influenza and human respiratory syncytial virus (HRSV) generate substantial extracellular HMGB1 release in pulmonary inflammation and that HMGB1-specific antagonists ameliorate these conditions (Ito et al 2011;Nosaka et al 2015;Nosaka et al 2018;Hatayama et al 2019;Manti et al 2018;Rayavara et al 2018;Rallabhandi et al 2012;Simpson et al 2020). Extracellular HMGB1 accumulates locally due to passive release from dying cells and active secretion from innate immunity cells and additional cell types.…”

“…Experimental RSV infections respond well to certain therapies that exert multiple biological effects, one of which includes HMGB1 antagonism. Two such examples are glycyrrhizin (Manti et al 2018) and the synthetic TLR4 antagonist eritoran (Rallabhandi et al 2012).…”

Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment

“…An increase in HMGB1 release has been observed during acute lung injury (ALI) under proinflammatory stimulation [66], but in the same model, autophagy stimulation was effective in reducing HMGB1 release and ALI. In fact, in preclinical and clinical studies, it has been demonstrated that RSV generates extracellular HMGB1 release in pulmonary inflammation and that HMGB1-specific antagonists ameliorate these conditions [67,68].…”