Potential Role of Soluble TRAIL in Epithelial Injury in Children with Severe RSV Infection

Abstract

Lower respiratory tract infection by respiratory syncytial virus (RSV) is a frequent cause of acute lung injury in young children and infants. Studies in adults and animals suggest that tumor necrosis factor receptor (TNFR) ligands may mediate lung injury by causing apoptosis of epithelial cells. The main goal of the present study was to determine whether the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) pathway may be implicated in epithelial injury during severe RSV infection in children. We report elevated levels of soluble (s)TRAIL released by leukocytes in bronchoalveolar lavage fluid (BALF) of patients with RSV-associated respiratory failure (n = 22) as compared with mechanically ventilated patients without pulmonary illness (n = 7). Primary bronchial epithelial cells of children without pulmonary disease obtained by nonbronchoscopic cytobrushing expressed both death receptors TRAIL-R1 and -R2, and were found to be susceptible for cell death by human recombinant sTRAIL in vitro. Furthermore, BALF from a patient with RSV induced cell death in these cells, which was partly attenuated by inhibiting TRAIL signaling. These data suggest that the TRAIL pro-apoptotic pathway may contribute to lung epithelial injury in severe RSV infection in children.

In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo

“…As a potent inducer of apoptosis (34), the high level of TRAIL induced by infection suggests that it is implicated in RSVinduced apoptosis and corresponds with its putative role in epithelial injury during severe RSV disease (35). Further work is necessary to elucidate the role of apoptosis and TRAIL in RSV pathogenesis.…”

“…When confluent, apical medium was removed to create an ALI. At 21 d post-ALI, when cultures formed a pseudostratified mucociliary epithelium with beating cilia and mucus production (Movie S4), they were infected in duplicate [multiplicity of infection (MOI) ∼4] with the prototypic RSV strain A2 or a recent clinical isolate, BT2a (35). The inocula or mediumonly controls were added to the apical surface of the cultures and incubated for 2 h at 37°C, 5% CO 2 .…”

Soluble TRAIL in normal pregnancy and acute pyelonephritis: a potential explanation for the susceptibility of pregnant women to microbial products and infection

“…neutrophils, monocytes, macrophages, CD4 + T cells, NK cells, and dendritic cells) [92–94]. Although most studies have examined the role of TRAIL in viral infections such as HIV [87,95,96], cytomegalovirus [97], influenza [98,99], reovirus [100] and respiratory syncytial virus [101], this protein is also involved in regulation of inflammatory response to bacterial infections [102]. Indeed, TRAIL and its receptors have been implicated in the removal of senescent circulating neutrophils and activated tissue neutrophils, leading to resolution of inflammation [23,24].…”

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

“…Interestingly, Trail − / − mice are unable to clear an IAV infection as well as wild-type mice, and Trail − / − mice are more susceptible to death from immunopathology after IAV infection (Brincks et al, 2008; Brincks et al, 2011). Additional data report increased TRAIL expression after infection with Dengue virus, hepatitis virus, human immunodeficiency virus, measles virus, respiratory syncytial virus, and West Nile virus contributes to both viral clearance and immunopathology (Bem et al, 2010; Stegmann et al, 2010; van Grevenynghe et al, 2011; Barblu et al, 2012; Shrestha et al, 2012; Abdullah et al, 2013; Gandini et al, 2013; Gras et al, 2013; Werner et al, 2013; Brost et al, 2014; Limonta et al, 2014). …”