At day 0, mice were infected with 5 106 PFU RSV. in the lung. This study suggests a potential therapeutic approach for RSV bronchiolitis based on selective blockade of TNFR1. Keywords: tumor necrosis factor, TNF, TNFR1, TNFR2, respiratory syncytial computer virus, RSV, bronchiolitis, bronchoconstriction, neutrophils, macrophages, BALF 1. Introduction Respiratory syncytial computer virus (RSV) is usually a negative-sense single stranded RNA computer virus of the family Pneumoviridae [1]. It is responsible for more than 33.1 million lesser respiratory tract infections each year, making it the leading cause of respiratory illness in children less than five years of age. Symptoms of RSV infections range in severity from moderate rhinorrhea to pneumonia [2]. The genome of RSV encodes eleven viral proteins, including two surface glycoproteins (RSV F and RSV G). Utilizing these proteins, RSV is able to invade Z-LEHD-FMK the epithelial lining of the nasopharynx with severe cases progressing down to the small Hmox1 conductive airways resulting in acute bronchiolitis [3]. This involves occlusion of the bronchiolar airways due to excessive inflammation and mucus secretion, necrosis of the bronchiolar epithelium, and peribronchiolar infiltration by numerous leukocytes [4,5]. Several longitudinal studies have linked RSV bronchiolitis to a heightened risk of recurrent wheezing and asthma within the first 10 years of life [6,7,8,9,10]. Clinical studies analyzing cytokine mediators in the bronchoalveolar lavage fluid (BALF) of patients with RSV bronchiolitis have implicated pro-inflammatory cytokines, including tumor necrosis factor (TNF)-, as a major contributor to disease [11,12,13]. As such, there is a growing need to develop anti-inflammatory strategies that target the cytokine storm associated with RSV infections, particularly those spreading to the lower respiratory tract. TNF-, a member of the TNF-superfamily (TNFSF), is a potent inflammatory mediator with key Z-LEHD-FMK roles in homeostasis and disease pathogenesis. Synthesized primarily by macrophages, TNF is initially expressed as a type II transmembrane protein until cleaved to its soluble form by the metalloproteinase TNF–converting enzyme (TACE) [14,15,16]. Once in circulation, TNF- mediates a variety of bioactivities by signaling through two distinct receptors: TNF-receptor (TNFR)1 and TNFR2 [17,18]. TNFR1 is widely expressed on nearly all cell types. TNFR2 is more restricted, with expression on only select lymphoid cells (CD4/CD8+ and regulatory T-cells), macrophages, myeloid-derived suppressor cells (MDSCs), endothelial cells, select neuronal subtypes, cardiomyocytes, and human mesenchymal stem cells [19,20,21]. As a member of the TNFR-superfamily (TNFRSF), both receptors have similar extracellular domains comprised of several cysteine-rich domains (CRD) with a pre-ligand binding assembly domain (PLAD) located at the distal end of the CRD to mediate formation of the active receptor complex [17]. The intracellular domains separate the two receptors into different subgroups of the TNFRSF. TNFR1 harbors the death domain (DD), making it a death receptor (DR). Through interactions with other DD signaling proteins, TNFR1 regulates cytotoxic signaling pathways (e.g., apoptosis and necroptosis) as well as mediate the activation of the nuclear factor kappa B (NF-B) Z-LEHD-FMK family and/or kinases of the MAP kinase family [14,17,22]. As with the patterns of expression, the intracellular domain of TNFR2 bears little resemblance to TNFR1. The cytoplasmic region of TNFR2 contains a short amino acid sequence that enables the recruitment of TNF receptor-associated factor (TRAF)-2 and its associated proteins (e.g., TRAF1, cellular inhibitor of apoptosis protein (cIAP)1 and cIAP2). Using these proteins, TNFR2 activates canonical and non-canonical NF-B pathways to promote cell survival and proliferation [14,17]. These downstream properties of TNFRs make them a prime candidate for therapeutic interventions aimed to block acute and chronic inflammation. Early studies in mouse models of RSV infection have examined the role of TNF- in disease and viral replication using strategies to block the soluble cytokine with neutralizing antibodies and showed some improvement in disease (body weight.
