Significant linkage at chromosome 19q for otitis media with effusion and/or recurrent otitis media (COME/ROM)

<p>Abstract</p> <p>Background</p> <p>In previous analyses, we identified a region of chromosome 19 as harboring a susceptibility locus for chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our aim was to further localize the linkage signal and ultimately identify the causative variant or variants. We followed up our previous linkage scan with dense SNP genotyping across in a 5 Mb region. A total of 607 individuals from 139 families, including 159 affected sib pairs and 62 second-degree affected relative pairs, were genotyped at 1,091 SNPs. We carried out a nonparametric linkage analysis, modeling marker-to-marker linkage disequilibrium.</p> <p>Results</p> <p>The maximum log of the odds (LOD) score increased to 3.75 (P = 1.6 × 10^-5) at position 63.4 Mb, with a LOD-1 support interval between 61.6 Mb and 63.8 Mb, providing significant evidence of linkage between this region and COME/ROM. The support interval contains over 90 known genes, including several genes involved in the inflammasome protein complex, a key regulator of the innate immune response to harmful exogenous or endogenous stimuli. Parametric linkage analysis suggests that for a sib of an affected individual, the recurrence risk of COME/ROM due to this linkage region is twice the recurrence risk in the population. We examined potential associations between the SNPs genotyped in this region and COME/ROM, however none provided evidence for association.</p> <p>Conclusion</p> <p>This study has refined the 19q region of linkage with COME/ROM, and association results suggest that the linkage signal may be due to rare variants.</p

Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4 (Nature, (2020), 587, 7834, (466-471), 10.1038/s41586-020-2877-5)

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. An amendment to this paper has been published and can be accessed via a link at the top of the paper

Exuberant fibroblast activity compromises lung function via ADAMTS4

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections

Human CD8+ T cell cross-reactivity across influenza A, B and C viruses

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8+ T cells confer cross-protection against IAV strains, however the responses of CD8+ T cells to IBV and ICV are understudied. We investigated the breadth of CD8+ T cell cross-recognition and provide evidence of CD8+ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8+ T cell epitopes from IBVs that were protective in mice and found memory CD8+ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8+ T cells displayed tissue-resident memory phenotypes. Notably, CD38+Ki67+CD8+ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8+ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines

Power was computed using TDT Power Calculator [15] varying SNP minor allele frequency (MAF) and genetic relative risk (GRR).

<p>Power was computed using TDT Power Calculator <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104212#pone.0104212-Chen1" target="_blank">[15]</a> varying SNP minor allele frequency (MAF) and genetic relative risk (GRR).</p

Secondary Graft Loss After Third-party "Off-The-Shelf" Antigen-Specific T cell Infusion

&lt;p&gt;Here, we describe a severe adverse event of virus-specific T cell (VST therapy) in an infant with severe combined immunodeficiency who received VSTs for treatment of CMV viremia post-transplant and developed secondary graft rejection at 1-month post-VST infusion associated with the expansion of VST donor-derived T cells. Deposited here are the bulk repertoire, single-cell gene expression and TCR, and flow cytometry data from the study.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;bulk_rep.zip contains tables of alpha/beta TCR sequences for post-infusion, VST donor, and VST product samples, and samples stimulated with neoepitope peptides.&nbsp;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;VST_agg_wTCR_SS.rds is an R Data Serialization file containing a Seurat object of the processed 10X single-cell gene expression and TCR profiling for the post-infusion, VST donor, and VST product samples. TCR information is stored in the meta.data slot.&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;P0230D neoantigen expansions.acs, P0230D pentamers.acs, and P0230D_MLR.acs contain the flow cytometry data for the neoantigen and mixed lymphocyte reaction experiments.&lt;/strong&gt;&lt;/p&gt