Age at First Viral Infection Determines the Pattern of T Cell–mediated Disease during Reinfection in Adulthood

Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lung pathology during subsequent rechallenge. Primary RSV infection in newborn mice followed the same viral kinetics as in adults but was associated with reduced and delayed IFN-γ responses. To study rechallenge, mice were infected at 1 day or 1, 4, or 8 weeks of age and reinfected at 12 weeks. Neonatal priming produced more severe weight loss and increased inflammatory cell recruitment (including T helper 2 cells and eosinophils) during reinfection, whereas delayed priming led to enhanced interferon γ production and less severe disease during reinfection. These results show the crucial importance of age at first infection in determining the outcome of reinfection and suggest that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life. Thus, simply delaying RSV infection beyond infancy might reduce subsequent respiratory morbidity in later childhood

OX40 Ligand and Programmed Cell Death 1 Ligand 2 Expression on Inflammatory Dendritic Cells Regulates CD4 T Cell Cytokine Production in the Lung during Viral Disease

CD4-T-helper-cell (Th) differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (DCs) in regional lymph nodes and results in specific patterns of cytokine production. However, the function of costimulatory molecules on ‘inflammatory’ (CD11b+) DCs in the lung during recall responses is not fully understood, but important for development of novel interventions to limit immunopathological responses to infection. Using a mouse model in which vaccination with vaccinia virus vectors expressing the respiratory syncytial virus (RSV) fusion protein (rVVF) or attachment protein (rVVG) leads to type 1- or type 2-biased cytokine responses respectively upon RSV-challenge, we found expression of CD40 and OX40L on lung inflammatory DCs was higher in rVVF- than in rVVG-primed mice early after RSV-challenge, while the reverse was observed later in the response. Conversely, PD-L2 was higher in rVVG-primed mice throughout. Inflammatory DCs isolated at the resolution of inflammation revealed OX40L on type 1-biased DCs promoted IL-5, while on type 2-biased DCs enhanced IFNγ production by antigen-reactive Th cells. In contrast, PD-L2 promoted IFNγ production irrespective of conditions, suppressing IL-5 only if expressed on type 1-biased DCs. Thus, OX40L and PD-L2 expressed on DCs differentially regulate cytokine production during recall responses in the lung. Manipulation of these costimulatory pathways may provide a novel approach to controlling pulmonary inflammatory responses

COVID-19 Pneumothorax in the United Kingdom: a prospective observational study using the ISARIC WHO clinical characterisation protocol.

Population level data from 131 679 patients show that COVID-19 pneumothorax occurs in 0.97% of admitted patients, especially males and smokers, and is associated with increased mortality

Toward unified molecular surveillance of RSV: A proposal for genotype definition

Background: Human respiratory syncytial virus (RSV) is classified into antigenic subgroups A and B. Thirteen genotypes have been defined for RSV-A and 20 for RSV-B, without any consensus on genotype definition. Methods: We evaluated clustering of RSV sequences published in GenBank until February 2018 to define genotypes by using maximum likelihood and Bayesian phylogenetic analyses and average p-distances. Results: We compared the patterns of sequence clustering of complete genomes; the three surface glycoproteins genes (SH, G, and F, single and concatenated); the ectodomain and the 2nd hypervariable region of G gene. Although complete genome analysis achieved the best resolution, the F, G, and G-ectodomain phylogenies showed similar topologies with statistical support comparable to complete genome. Based on the widespread geographic representation and large number of available G-ectodomain sequences, this region was chosen as the minimum region suitable for RSV genotyping. A genotype was defined as a monophyletic cluster of sequences with high statistical support (≥80% bootstrap and ≥0.8 posterior probability), with an intragenotype p-distance ≤0.03 for both subgroups and an intergenotype p-distance ≥0.09 for RSV-A and ≥0.05 for RSV-B. In this work, the number of genotypes was reduced from 13 to three for RSV-A (GA1-GA3) and from 20 to seven for RSV-B (GB1-GB7). Within these, two additional levels of classification were defined: subgenotypes and lineages. Signature amino acid substitutions to complement this classification were also identified. Conclusions: We propose an objective protocol for RSV genotyping suitable for adoption as an international standard to support the global expansion of RSV molecular surveillance.Fil: Goya, Stephanie. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Laboratorio de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Galiano, Mónica. Public Health England; Reino UnidoFil: Nauwelaers, Inne. Imperial College London; Reino UnidoFil: Trento, Alfonsina. Instituto de Investigación Hospital 12 de Octubre; EspañaFil: Openshaw, Peter J.. Imperial College London; Reino UnidoFil: Mistchenko, Alicia Susana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Laboratorio de Virología; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Zambon, Maria. Public Health England; Reino UnidoFil: Viegas, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Laboratorio de Virología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Predicted Public Health and Economic Impact of Respiratory Syncytial Virus Vaccination with Variable Duration of Protection for Adults ≥60 Years in Belgium

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection (ARI) in older adults. This study used a static, cohort-based decision-tree model to estimate the public health and economic impact of vaccination against RSV in Belgians aged ≥60 years compared with no vaccination for different vaccine duration of protection profiles from a healthcare payer perspective. Three vaccine protection durations were compared (1, 3, and 5 years), and several sensitivity and scenario analyses were performed. Results showed that an RSV vaccine with a 3-year duration of protection would prevent 154,728 symptomatic RSV-ARI cases, 3688 hospitalizations, and 502 deaths over three years compared to no vaccination in older adults and would save EUR 35,982,857 in direct medical costs in Belgium. The number needed to vaccinate to prevent one RSV-ARI case was 11 for the 3-year duration profile, while it was 28 and 8 for the 1- and 5-year vaccine duration profiles, respectively. The model was generally robust in sensitivity analyses varying key input values. This study suggested that vaccination could substantially decrease the public health and economic burden of RSV in adults ≥60 years in Belgium, with benefits increasing with a longer duration of vaccine protection.</p

Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice, and humans.

We compared live zebrafish, mouse and human nasal challenge responses to the TLR7/8 agonist resiquimod (R848). We found remarkably similar induction of mediators in the three species, offering novel mucosal models of innate anti-viral immunity

The Chemokine MIP1α/CCL3 Determines Pathology in Primary RSV Infection by Regulating the Balance of T Cell Populations in the Murine Lung

BACKGROUND: CD8 T cells assist in the clearance of respiratory syncytial virus (RSV) infection from the lungs. However, disease after RSV infection is in part caused by excessive T cell activity, and a balance is therefore needed between beneficial and harmful cellular immune responses. The chemokine CCL3 (MIP1alpha) is produced following RSV infection and is broadly chemotactic for both T cells and natural killer (NK) cells. We therefore investigated its role in RSV disease. METHODOLOGY/PRINCIPAL FINDINGS: CCL3 was produced biphasically, in both the early (day 1) and late (day 6-7) stages of infection. CCL3 depletion did not alter the recruitment of natural killer (NK) cells to the lungs during the early stage, but depletion did affect the later adaptive phase. While fewer T cells were recruited to the lungs of either CCL3 knockout or anti-CCL3 treated RSV infected mice, more RSV-specific pro-inflammatory T cells were recruited to the lung when CCL3 responses were impaired. This increase in RSV-specific pro-inflammatory T cells was accompanied by increased weight loss and illness after RSV infection. CONCLUSIONS/SIGNIFICANCE: CCL3 regulates the balance of T cell populations in the lung and can alter the outcome of RSV infection. Understanding the role of inflammatory mediators in the recruitment of pathogenic T cells to the lungs may lead to novel methods to control RSV disease

Patterns of systemic and local inflammation in patients with asthma hospitalised with influenza.

BACKGROUND: Patients with asthma are at risk of hospitalisation with influenza, but the reasons for this predisposition are unknown. STUDY SETTING: A prospective observational study of adults with PCR-confirmed influenza in 11 UK hospitals, measuring nasal, nasopharyngeal and systemic immune mediators and whole-blood gene expression. RESULTS: Of 133 admissions, 40 (30%) had previous asthma; these were more often female (70% versus 38.7%, OR 3.69, 95% CI 1.67 to 8.18, p=0.0012), required less mechanical ventilation (15% versus 37.6%, χ2 6.78, p=0.0338) and had shorter hospital stays (mean 8.3 versus 15.3 d, p=0.0333) than those without. In patients without asthma, severe outcomes were more frequent in those given corticosteroids (OR=2.63, 95% CI=1.02-6.96, p=0.0466) or presenting >4 days after disease onset (OR 5.49, 95% CI 2.28-14.03, p=0.0002). Influenza vaccination in at-risk groups (including asthma) were lower than intended by national policy and the early use of antiviral medications were less than optimal. Mucosal immune responses were equivalent between groups. Those with asthma had higher serum IFN-α but lower serum TNF, IL-5, IL-6, CXCL8, CXCL9, IL-10, IL-17 and CCL2 levels (all p<0.05); both groups had similar serum IL-13, total IgE, periostin and blood eosinophil gene expression levels. Asthma diagnosis was unrelated to viral load, IFN-α, IFN-γ, IL-5 or IL-13 levels. CONCLUSIONS: Asthma is common in those hospitalised with influenza, but may not represent classical Type 2-driven disease. Those admitted with influenza tend to be female with mild serum inflammatory responses, increased serum IFN-α levels and good clinical outcomes.MOSAIC (Mechanisms of Severe Influenza Consortium) was supported by the MRC (UK) and Wellcome Trust (090382/Z/09/Z). The study was also supported by the National Institute of Healthcare Research (NIHR) Biomedical Research Centres (BRCs) in London and Liverpool and by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Respiratory Infections at Imperial College London in partnership with Public Health England (PHE). P.J.O. was supported by EU FP7 PREPARE project 602525