prostaglandin-d2 and Respiratory-Syncytial-Virus-Infections

Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

Topics: Allergens; Animals; Animals, Newborn; Antiviral Agents; Bronchiolitis, Viral; Epithelial Cells; Humans; Immunity; Infant; Inflammation; Interferon-gamma; Intramolecular Oxidoreductases; Lung; Mice, Inbred BALB C; Murine pneumonia virus; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Up-Regulation

During respiratory viral infection, conventional dendritic cells (cDCs) take up antigen and migrate to the draining lymph nodes to present viral antigen and activate cytotoxic T lymphocytes; however, regulation of cDC activation and migration may be age dependent. In this study, we used a mouse model of paramyxoviral infection (Sendai virus) and demonstrated that cDCs, which have migrated from lungs to the draining lymph nodes, are delayed in expressing activation markers in neonatal mice compared with adults. Neonatal lung cDCs expressed reduced levels of MHC Class II (major histocompatibility complex II) and CCR7 (chemokine receptor type 7) on postinfection days 3 and 5, respectively. The level of the CCR7 ligand CCL19 was significantly reduced in neonatal lungs during the course of viral infection. Interestingly, the arachidonic acid metabolite prostaglandin D

Topics: Animals; Animals, Newborn; Antigens, CD; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytokines; Dendritic Cells; Disease Models, Animal; Epithelial Cells; Humans; Integrin alpha Chains; Intramolecular Oxidoreductases; Lipocalins; Lung; Mice; Primary Cell Culture; Prostaglandin D2; Receptors, CCR7; Receptors, Prostaglandin; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Thymic Stromal Lymphopoietin; Trachea

The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell-extrinsic functions. Here, we show that increases in prostaglandin D(2) (PGD(2)) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration associated with virus-specific defects in T cell responses and was not a result of cell-intrinsic defect, rather it reflected the observed age-dependent increases in PGD(2) expression. Blocking PGD(2) function with small-molecule antagonists enhanced rDC migration, T cell responses, and survival. This effect correlated with upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. Our results suggest that inhibiting PGD(2) function may be a useful approach to enhance T cell responses against respiratory viruses in older humans.

Topics: Aging; Animals; Cell Movement; Cellular Microenvironment; Coronavirus Infections; Dendritic Cells; Disease Susceptibility; Immunocompromised Host; Influenza A virus; Lung; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Murine hepatitis virus; Orthomyxoviridae Infections; Prostaglandin Antagonists; Prostaglandin D2; Receptors, CCR7; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets

Decline in immune function with age has been attributed to defects or alterations in both the innate and the adaptive immune system. In this issue of the JCI, Zhao and coworkers provide evidence for a novel mechanism of immune dysfunction in aging mice. They show that migration of respiratory DCs from the site of virus replication to the draining lymph nodes in response to infection with several different respiratory viruses is markedly diminished with increasing age. The impaired DC migration was a result of increased levels of the lipid mediator prostaglandin D(2) (PGD(2)) in the respiratory tract with age and could be partially reversed by blockade of PGD(2) synthesis or action.

Topics: Aging; Animals; Coronavirus Infections; Dendritic Cells; Orthomyxoviridae Infections; Prostaglandin D2; Respiratory Syncytial Virus Infections; T-Lymphocyte Subsets

Respiratory syncytial virus (RSV) is the major causative agent of severe lower respiratory tract disease and death in infants worldwide. The epithelial cells of the airways are the target cells for RSV infection and the site of the majority of the inflammation associated with the disease. However, despite five decades of intensive RSV research there exist neither an effective active vaccine nor a promising antiviral and anti-inflammatory therapy. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we hypothesized whether the detrimental increase of intercellular adhesion molecule-1 (ICAM-1) on RSV-infected lung epithelial cells (A549 and primary normal human bronchial epithelial cells (NHBE)) might be modulated by natural and synthetic PPAR-gamma agonists (15d-PGJ2, ciglitazone, troglitazone, Fmoc-Leu). Our data show that all PPAR-gamma agonists under study significantly down-regulated the RSV-induced expression of ICAM-1 on A549- and NHBE cells in a dose-dependent manner resulting in a reduced beta2 integrin-mediated adhesion of monocytic effector cells (U937) to RSV-infected A549 cell monolayers. In contrast, the PPAR-alpha agonist bezafibrate had no impact on the RSV-induced ICAM-1 expression. The reduced ICAM-1 expression was associated with a diminished ICAM-1 mRNA level and binding activity of nuclear factor-kappaB (p65/p50) in A549 cells. These findings suggest that PPARgamma agonists have beneficial effects in the suppression of the inflammatory response during RSV infection and therefore might have clinical efficacy in the course of severe RSV-infection.

Topics: Amino Acids; Cell Adhesion; Cell Line; Cells, Cultured; Chromans; Dose-Response Relationship, Drug; Down-Regulation; Epithelial Cells; Fluorenes; Humans; Intercellular Adhesion Molecule-1; Lung; NF-kappa B; PPAR gamma; Prostaglandin D2; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones; Troglitazone; U937 Cells