#Sepsis-associated #ARDS in individuals of #European #ancestry: a #genome-wide association study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Sepsis-associated acute respiratory distress syndrome in individuals of European ancestry: a genome-wide association study

Beatriz Guillen-Guio, MSc, Jose M Lorenzo-Salazar, MSc, Shwu-Fan Ma, PhD, Pei-Chi Hou, PhD, Tamara Hernandez-Beeftink, MSc, Almudena Corrales, LT, M Isabel García-Laorden, PhD, Jonathan Jou, MD, Elena Espinosa, MD, Arturo Muriel, MD, David Domínguez, MD, Leonardo Lorente, MD, María M Martín, MD, Carlos Rodríguez-Gallego, MD, Jordi Solé-Violán, MD, Alfonso Ambrós, MD, Demetrio Carriedo, MD, Jesús Blanco, MD, José M Añón, MD, John P Reilly, MD, Tiffanie K Jones, MD, Caroline AG Ittner, PhD, Rui Feng, PhD, Franziska Schöneweck, MSc, Michael Kiehntopf, MD, Imre Noth, MD, Markus Scholz, PhD, Frank M Brunkhorst, MD, André Scherag, PhD, Nuala J Meyer, MD, Jesús Villar, MD, Carlos Flores, PhD

Published: January 23, 2020 / DOI: https://doi.org/10.1016/S2213-2600(19)30368-6

 

Summary

Background

Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.

Methods

We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008–Nov 30, 2017; USA) and the VISEP (April 1, 2003–June 30, 2005) and MAXSEP (Oct 1, 2007–March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.

Findings

We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41–0·91, p=5·18 × 10 −8) located within the Fms-related tyrosine kinase 1 ( FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A ( VEGFA; OR 0·55, 95% CI 0·41–0·73; p=4·69 × 10 −5).

Interpretation

A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.

Funding

Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.

Keywords: ARDS; Sepsis; Genetics.

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A #classification #framework for #Bacillus anthracis defined by global #genomic structure (Evol Appl., abstract)

[Source: Evolutionary Applications, full page: (LINK). Abstract, edited.]

A classification framework for Bacillus anthracis defined by global genomic structure

Spencer A. Bruce,  Nicholas J. Schiraldi,  Pauline L. Kamath,  W. Ryan Easterday, Wendy C. Turner

First published: 23 December 2019 / DOI:  https://doi.org/10.1111/eva.12911

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/eva.12911

 

Abstract

Bacillus e, the causative agent of anthrax, is a considerable global health threat affecting wildlife, livestock, and the general public. In this study whole‐genome sequence analysis of over 350 B. anthracis isolates was used to establish a new high‐resolution global genotyping framework that is both biogeographically informative, and compatible with multiple genomic assays. The data presented in this study shed new light on the diverse global dissemination of this species and indicate that many lineages may be uniquely suited to the geographic regions in which they are found. In addition, we demonstrate that plasmid genomic structure for this species is largely consistent with chromosomal population structure, suggesting vertical inheritance in this bacterium has contributed to its evolutionary persistence. This classification methodology is the first based on population genomic structure for this species and has potential use for local and broader institutions seeking to understand both disease outbreak origins and recent introductions. In addition, we provide access to a newly developed genotyping script as well as the full whole‐genome sequence analyses output for this study, allowing future studies to rapidly employ and append their data in the context of this global collection. This framework may act as a powerful tool for public health agencies, wildlife disease laboratories, and researchers seeking to utilize and expand this classification scheme for further investigations into B. anthracis evolution.

Keywords: Bacillus anthracis; Anthrax; Genetics; Evolution.

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SCN1A #variants in #vaccine‐related febrile #seizures: a prospective study (Ann Neurol., abstract)

[Source: Annals of Neurology, full page: (LINK). Abstract, edited.]

SCN1A variants in vaccine‐related febrile seizures: a prospective study

JA Damiano,  L Deng,  WH Li,  R Burgess,  AL Schneider,  NW Crawford,  J Buttery, M Gold,  P Richmond,  KK Macartney,  MS Hildebrand,  IE Scheffer,  N Wood,  SF Berkovic

First published: 22 November 2019 / DOI:  https://doi.org/10.1002/ana.25650

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/ana.25650.

 

Abstract

Objective

Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet Syndrome. Following vaccination, febrile seizures may raise the spectre of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination, or unrelated to vaccination compared to controls.

Methods

We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n=69), or as non‐vaccine proximate (n=75), and children with no history of seizures (n=90) recruited in Australian paediatric hospitals.

Results

We detected two pathogenic variants in vaccine proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and one in a non‐vaccine proximate case (p.V947L) who had Febrile seizures plus from 9 months. All had generalised tonic‐clonic seizures lasting longer than 15 minutes. We also found enrichment of a reported risk allele, rs6432860‐T, in children with febrile seizures compared to controls (Odds Ratio 1.91 [95% CI 1.31‐ 2.81]).

Interpretation

Pathogenic SCN1A variants may be identified in infants with vaccine proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome. SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine.

This article is protected by copyright. All rights reserved.

Keywords: Drugs Safety; Vaccines; Genetics; Pediatrics; Encephalopathy; Australia.

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#Characteristics of #H7N9 #avian #influenza #pneumonia: a retrospective analysis of 17 cases (Inter Med J., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Intern Med J. 2019 Nov 10. doi: 10.1111/imj.14685. [Epub ahead of print]

Characteristics of H7N9 avian influenza pneumonia: a retrospective analysis of 17 cases.

Yu WQ1,2, Ji NF1, Ding MD2, Gu CJ3, Ma Y1, Wu ZZ1, Wang YL1, Wu CJ1, Dai GH4, Chen Y4, Jin RR4, Tan YB5, Yang Z6, Zhou DM2, Xian JC2, Xu HT2, Huang M1.

Author information: 1 Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. 2 Department of Infectious Diseases, Taizhou People’s hospital, Taizhou, 225300, China. 3 Department of Pharmacy, Taizhou People’s hospital, Taizhou, 225300, China. 4 Department of Pathology, Taizhou People’s hospital, Taizhou, 225300, China. 5 Department of Nuclear Medicine, Taizhou People’s hospital, Taizhou, 225300, China. 6 Department of Medical Microbiology and Immunology, Wannan Medical College, No. 22, Wenchang West Road, Yijiang District, Wuhu, Anhui, 241002, China.

 

Abstract

BACKGROUND:

H7N9 avian influenza is an infection of public health concern, in part because of its high mortality rate and pandemic potential.

OBJECTIVES:

We aimed to describe the clinical features of H7N9 avian influenza and the response to treatment.

METHODS:

Clinical, radiological, and histopathological data, and treatment-related of H7N9-infected patients hospitalized during 2014-2017 were extracted and analyzed.

RESULTS:

A total of 17 H7N9 patients (three females; mean age, 58.4 ± 13.7 years) were identified; of these six died. All patients presented with fever and productive cough; four patients had hemoptysis and 13 had chest distress and/or shortness of breath. Early subnormal white blood cell count and elevation of serum liver enzymes were common. Multilobar patchy shadows, rapid progression to ground-glass opacities, air bronchograms, and consolidation were the most common imaging findings. Histopathological examination of lung tissue of three patients who died showed severe alveolar epithelial cell damage, with inflammatory exudation into the alveolar space and hyaline membrane formation; widened alveolar septae, prominent inflammatory cell infiltration; and hyperplasia of pneumocytes. Viral inclusions were found in the lung tissue of two patients. All patients received antiviral drugs (oseltamivir ± peramivir). Four patients carried the rs12252-C/C IFN-induced transmembrane protein-3 (IFITM3) genotype, while the others had the C/T genotype.

CONCLUSIONS:

H7N9 virus infection causes human influenza-like symptoms, but may rapidly progress to severe pneumonia and even death. Clinicians should be alert to the possibility of H7N9 infection in high-risk patients. The presence of the IFITM3 rs12252-C genotype may predict severe illness.

This article is protected by copyright. All rights reserved.

PMID: 31707755 DOI: 10.1111/imj.14685

Keywords: Avian Influenza; H7N9; Human; China; Genetics.

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An #Evolutionary #Insight into Emerging #Ebolavirus #Strains Isolated in #Africa (J Med Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Med Virol. 2019 Nov 8. doi: 10.1002/jmv.25627. [Epub ahead of print]

An Evolutionary Insight into Emerging Ebolavirus Strains Isolated in Africa.

Pereira-Gomez M1,2, Lopez-Tort F3, Fajardo A1, Cristina J1.

Author information: 1 Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Iguá 4225, Montevideo, 11400, Uruguay. 2 Laboratorio de Inmunovirología, Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay. 3 Laboratorio de Virología Molecular, Sede Salto, Centro Universitario Regional Litoral Norte, Universidad de la República, Gral. Rivera 1350, 50000, Salto, Uruguay.

 

Abstract

BACKGROUND:

On July 19th, 2019, the World Health Organization declared the current Ebola virus (EBOV) outbreak in Congo Democratic Republic (COD) a public health emergency of international concern. To address the potential threat of EBOV evolution outpacing antibody treatment and vaccine efforts, a detailed evolutionary analysis of EBOV strains circulating in different African countries was performed.

METHODS:

Genome composition of EBOV strains were studied using multivariate statistical analysis. To investigate the patterns of evolution of EBOV strains, a Bayesian Markov Chain Monte Carlo (MCMC) approach was used.

RESULTS:

Two different genetic lineages, with a distinct genome composition gave rise to the recent EBOV outbreaks in central and western Africa. Strains isolated in COD in 2018 fall into two different genetic clusters, according to their geographical location of isolation. Different amino acid substitutions among strains from these two clusters have been found, particularly in NP, GP and L proteins. Significant differences in codon and amino acid usage among clusters were found.

CONCLUSION:

Strains isolated in COD in 2018 belongs to two distinct genetic clusters, with distinct codon and amino acid usage. Geographical diversity plays an important role in shaping the molecular evolution of EBOV populations.

This article is protected by copyright. All rights reserved.

KEYWORDS: Ebolavirus; GP protein; codon usage; evolution

PMID: 31702053 DOI: 10.1002/jmv.25627

Keywords: Ebolavirus; Ebola; DRC; Genetics.

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#Genomic #Epidemiology as a #PublicHealth #Tool to Combat #Mosquito-Borne Virus #Outbreaks (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Genomic Epidemiology as a Public Health Tool to Combat Mosquito-Borne Virus Outbreaks

S Pollett, J R Fauver, Irina Maljkovic Berry, M Melendrez, A Morrison, L D Gillis, M A Johansson, R G Jarman, N D Grubaugh

The Journal of Infectious Diseases, jiz302, https://doi.org/10.1093/infdis/jiz302

Published: 10 November 2019

 

Abstract

Next-generation sequencing technologies, exponential increases in the availability of virus genomic data, and ongoing advances in phylogenomic methods have made genomic epidemiology an increasingly powerful tool for public health response to a range of mosquito-borne virus outbreaks. In this review, we offer a brief primer on the scope and methods of phylogenomic analyses that can answer key epidemiological questions during mosquito-borne virus public health emergencies. We then focus on case examples of outbreaks, including those caused by dengue, Zika, yellow fever, West Nile, and chikungunya viruses, to demonstrate the utility of genomic epidemiology to support the prevention and control of mosquito-borne virus threats. We extend these case studies with operational perspectives on how to best incorporate genomic epidemiology into structured surveillance and response programs for mosquito-borne virus control. Many tools for genomic epidemiology already exist, but so do technical and nontechnical challenges to advancing their use. Frameworks to support the rapid sharing of multidimensional data and increased cross-sector partnerships, networks, and collaborations can support advancement on all scales, from research and development to implementation by public health agencies.

Topic: epidemiology – dengue fever – culicidae – disease outbreaks – genome – yellow fever – public health medicine – viruses – surveillance, medical – zika virus

Issue Section: supplement articles

Keywords: Arbovirus; Public Health; Mosquitoes; Genetics.

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#Genetic diversity of Collaborative Cross mice controls viral #replication, clinical #severity and #brain #pathology induced by #Zika virus #infection, independently of Oas1b (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b.

Caroline Manet, Etienne Simon-Lorière, Grégory Jouvion, David Hardy, Matthieu Prot, Laurine Conquet, Marie Flamand, Jean-Jacques Panthier, Anavaj Sakuntabhai, Xavier Montagutelli

DOI: 10.1128/JVI.01034-19

 

ABSTRACT

The explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1 knockout mice is largely influenced by their genetic background. We then show that the broad genetic diversity of Collaborative Cross mice, of which receptor to type I interferon (IFNAR) was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences in susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results rule out a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, this study emphasizes the role of host genes in the pathogeny of ZIKV infection and lays the foundation for further genetic and mechanistic studies.

 

IMPORTANCE

In recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barré syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in mediating the clinical heterogeneity remains mostly unexplored. We have addressed this question using a mouse panel which models the genetic diversity of human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells, and clinical severity, kinetics of blood viral load and brain pathology in mice. We describe new mouse models expressing high susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Zika Virus; Viral pathogenesis; Genetics; Neuroinvasion; Animal models.

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