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Host Infectomics in the Childhood

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 26829

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Prof. Dr. Antonio Salas

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Departamento de Anatomía Patolóxica e Ciencias Forenses, Instituto de Ciencias Forenses, Facultade de Medicina, University of Santiago de Compostela, Galicia, Spain
Interests: genetics; genomics; transcriptomics; epigenomics; exomes; complete genomes; ultrasequencing; NGS; DNA polymorphisms; single nucleotide polymorphism; SNP; short tandem repeat; STR; autosomes; complex multifactorial diseases; rare diseases; population genetics; evolutionary genetics
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Dear Colleagues,

Despite the availability of new vaccines and antibacterial agents suppressing microbial pathogens, infectious diseases are among the leading cause of morbidity and mortality worldwide. While there are a number of studies dealing with infections in adults (mainly focused on some particular diseases, e.g., tuberculosis) and/or pathogens, less attention has been devoted to the pediatric age. To overcome this deficiency, several international consortia have emerged in the last decade aimed at investigating life-threatening infections affecting childhood.

‘Omic’ sciences are gaining growing attention in parallel with the development of new and cost-effective technologies, but also bioinformatic and mathematical solutions that allow dealing with big data from massive genotyping and sequencing technologies. The field of infectiology is one of the many in biomedicine that is benefiting from these new achievements, and in particular, the area studying host response to infection from different ‘omic’ perspectives, namely, host infectomics. Thus, there is now increasing evidence supporting that it is not only the pathogen that decides how and when to infect the host, but also the biological predisposition of the host to be infected by the pathogen. Most of the genomic studies published to date have focused their attention on genomics, first by exploring a few thousands of single nucleotide polymorphisms (SNPs) distributed throughout the whole genome in large case-control samples (e.g., population-based genome-wide association studies; GWAS), and more recently using parallel sequencing procedures (e.g., whole exome sequencing, WES). There are also interesting attempts in the terrain of transcriptomic, using microarrays and more recently RNAseq, to investigate the host genetic expression response to different infections and pathogens.

We invite researchers to contribute original research articles and reviews focused on host infectomics in children. Topics of interest include but are not limited to the following:

Genomics, transcriptomics, epigenomics, proteomics, etc.;
Systems biology;
Studies exploring big data resources and using discovery-based procedures and providing insights on host biomarkers for infections.

Prof. Dr. Antonio Salas
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Host infectomics
Genomics
Transcriptomics
Systems biology
Biomarkers

Published Papers (7 papers)

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Research

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24 pages, 10507 KiB

Open AccessArticle

Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles

by Heather Jackson, Stephanie Menikou, Shea Hamilton, Andrew McArdle, Chisato Shimizu, Rachel Galassini, Honglei Huang, Jihoon Kim, Adriana Tremoulet, Adam Thorne, Roman Fischer, Marien I. de Jonge, Taco Kuijpers, Victoria Wright, Jane C. Burns, Climent Casals-Pascual, Jethro Herberg, Mike Levin, Myrsini Kaforou and on behalf of the PERFORM Consortium

Int. J. Mol. Sci. 2021, 22(11), 5655; https://doi.org/10.3390/ijms22115655 - 26 May 2021

Cited by 6 | Viewed by 3927

Abstract

The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host ‘omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple ‘omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of ‘omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both ‘omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both ‘omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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11 pages, 711 KiB

Open AccessArticle

Identification of a Minimal 3-Transcript Signature to Differentiate Viral from Bacterial Infection from Best Genome-Wide Host RNA Biomarkers: A Multi-Cohort Analysis

by Alberto Gómez-Carballa, Ruth Barral-Arca, Miriam Cebey-López, Xabier Bello, Jacobo Pardo-Seco, Federico Martinón-Torres and Antonio Salas

Int. J. Mol. Sci. 2021, 22(6), 3148; https://doi.org/10.3390/ijms22063148 - 19 Mar 2021

Cited by 4 | Viewed by 2497

Abstract

The fight against the spread of antibiotic resistance is one of the most important challenges facing health systems worldwide. Given the limitations of current diagnostic methods, the development of fast and accurate tests for the diagnosis of viral and bacterial infections would improve patient management and treatment, as well as contribute to reducing antibiotic misuse in clinical settings. In this scenario, analysis of host transcriptomics constitutes a promising target to develop new diagnostic tests based on the host-specific response to infections. We carried out a multi-cohort meta-analysis of blood transcriptomic data available in public databases, including 11 different studies and 1209 samples from virus- (n = 695) and bacteria- (n = 514) infected patients. We applied a Parallel Regularized Regression Model Search (PReMS) on a set of previously reported genes that distinguished viral from bacterial infection to find a minimum gene expression bio-signature. This strategy allowed us to detect three genes, namely BAFT, ISG15 and DNMT1, that clearly differentiate groups of infection with high accuracy (training set: area under the curve (AUC) 0.86 (sensitivity: 0.81; specificity: 0.87); testing set: AUC 0.87 (sensitivity: 0.82; specificity: 0.86)). BAFT and ISG15 are involved in processes related to immune response, while DNMT1 is related to the preservation of methylation patterns, and its expression is modulated by pathogen infections. We successfully tested this three-transcript signature in the 11 independent studies, demonstrating its high performance under different scenarios. The main advantage of this three-gene signature is the low number of genes needed to differentiate both groups of patient categories. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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14 pages, 1104 KiB

Open AccessArticle

The Feasibility of Host Transcriptome Profiling as a Diagnostic Tool for Microbial Etiology in Childhood Cancer Patients with Febrile Neutropenia

by Martina Wahlund, Indranil Sinha, Kristina Broliden, Shanie Saghafian-Hedengren, Anna Nilsson and Anna Berggren

Int. J. Mol. Sci. 2020, 21(15), 5305; https://doi.org/10.3390/ijms21155305 - 26 Jul 2020

Cited by 11 | Viewed by 2090

Abstract

Infection is a common and serious complication of cancer treatment in children that often presents as febrile neutropenia (FN). Gene-expression profiling techniques can reveal transcriptional signatures that discriminate between viral, bacterial and asymptomatic infections in otherwise healthy children. Here, we examined whether gene-expression profiling was feasible in children with FN who were undergoing cancer treatment. The blood transcriptome of the children (n = 63) was investigated at time of FN diagnosed as viral, bacterial, co-infection or unknown etiology, respectively, and compared to control samples derived from 12 of the patients following the FN episode. RNA sequencing was successful in 43 (68%) of the FN episodes. Only two genes were significantly differentially expressed in the bacterial versus the control group. Significantly up-regulated genes in patients with the other three etiologies versus the control group were enriched with cellular processes related to proliferation and cellular stress response, with no clear enrichment with innate responses to pathogens. Among the significantly down-regulated genes, a few clustered into pathways connected to responses to infection. In the present study of children during cancer treatment, the blood transcriptome was not suitable for determining the etiology of FN because of too few circulating immune cells for reliable gene expression analysis. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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13 pages, 1030 KiB

Open AccessArticle

RNA-Seq Data-Mining Allows the Discovery of Two Long Non-Coding RNA Biomarkers of Viral Infection in Humans

by Ruth Barral-Arca, Alberto Gómez-Carballa, Miriam Cebey-López, María José Currás-Tuala, Sara Pischedda, Sandra Viz-Lasheras, Xabier Bello, Federico Martinón-Torres and Antonio Salas

Int. J. Mol. Sci. 2020, 21(8), 2748; https://doi.org/10.3390/ijms21082748 - 15 Apr 2020

Cited by 6 | Viewed by 4313

Abstract

There is a growing interest in unraveling gene expression mechanisms leading to viral host invasion and infection progression. Current findings reveal that long non-coding RNAs (lncRNAs) are implicated in the regulation of the immune system by influencing gene expression through a wide range of mechanisms. By mining whole-transcriptome shotgun sequencing (RNA-seq) data using machine learning approaches, we detected two lncRNAs (ENSG00000254680 and ENSG00000273149) that are downregulated in a wide range of viral infections and different cell types, including blood monocluclear cells, umbilical vein endothelial cells, and dermal fibroblasts. The efficiency of these two lncRNAs was positively validated in different viral phenotypic scenarios. These two lncRNAs showed a strong downregulation in virus-infected patients when compared to healthy control transcriptomes, indicating that these biomarkers are promising targets for infection diagnosis. To the best of our knowledge, this is the very first study using host lncRNAs biomarkers for the diagnosis of human viral infections. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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14 pages, 1826 KiB

Open AccessArticle

A Meta-Analysis of Multiple Whole Blood Gene Expression Data Unveils a Diagnostic Host-Response Transcript Signature for Respiratory Syncytial Virus

by Ruth Barral-Arca, Alberto Gómez-Carballa, Miriam Cebey-López, Xabier Bello, Federico Martinón-Torres and Antonio Salas

Int. J. Mol. Sci. 2020, 21(5), 1831; https://doi.org/10.3390/ijms21051831 - 6 Mar 2020

Cited by 18 | Viewed by 4029

Abstract

Respiratory syncytial virus (RSV) is one of the major causes of acute lower respiratory tract infection worldwide. The absence of a commercial vaccine and the limited success of current therapeutic strategies against RSV make further research necessary. We used a multi-cohort analysis approach to investigate host transcriptomic biomarkers and shed further light on the molecular mechanism underlying RSV-host interactions. We meta-analyzed seven transcriptome microarray studies from the public Gene Expression Omnibus (GEO) repository containing a total of 922 samples, including RSV, healthy controls, coronaviruses, enteroviruses, influenzas, rhinoviruses, and coinfections, from both adult and pediatric patients. We identified > 1500 genes differentially expressed when comparing the transcriptomes of RSV-infected patients against healthy controls. Functional enrichment analysis showed several pathways significantly altered, including immunologic response mediated by RSV infection, pattern recognition receptors, cell cycle, and olfactory signaling. In addition, we identified a minimal 17-transcript host signature specific for RSV infection by comparing transcriptomic profiles against other respiratory viruses. These multi-genic signatures might help to investigate future drug targets against RSV infection. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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Review

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19 pages, 1258 KiB

Open AccessReview

Pediatric Tuberculosis: The Impact of “Omics” on Diagnostics Development

by Shailja Jakhar, Alexis A. Bitzer, Loreen R. Stromberg and Harshini Mukundan

Int. J. Mol. Sci. 2020, 21(19), 6979; https://doi.org/10.3390/ijms21196979 - 23 Sep 2020

Cited by 11 | Viewed by 5323

Abstract

Tuberculosis (TB) is a major public health concern for all ages. However, the disease presents a larger challenge in pediatric populations, partially owing to the lack of reliable diagnostic standards for the early identification of infection. Currently, there are no biomarkers that have been clinically validated for use in pediatric TB diagnosis. Identification and validation of biomarkers could provide critical information on prognosis of disease, and response to treatment. In this review, we discuss how the “omics” approach has influenced biomarker discovery and the advancement of a next generation rapid point-of-care diagnostic for TB, with special emphasis on pediatric disease. Limitations of current published studies and the barriers to their implementation into the field will be thoroughly reviewed within this article in hopes of highlighting future avenues and needs for combating the problem of pediatric tuberculosis. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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19 pages, 1001 KiB

Open AccessReview

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

by James F. Read and Anthony Bosco

Int. J. Mol. Sci. 2020, 21(17), 6372; https://doi.org/10.3390/ijms21176372 - 2 Sep 2020

Cited by 11 | Viewed by 4116

Abstract

Human Respiratory Syncytial Virus and Human Rhinovirus are the most frequent cause of respiratory tract infections in infants and children and are major triggers of acute viral bronchiolitis, wheezing and asthma exacerbations. Here, we will discuss the application of the powerful tools of systems biology to decode the molecular mechanisms that determine risk for infection and subsequent asthma. An important conceptual advance is the understanding that the innate immune system is governed by a Bow-tie architecture, where diverse input signals converge onto a few core pathways (e.g., IRF7), which in turn generate diverse outputs that orchestrate effector and regulatory functions. Molecular profiling studies in children with severe exacerbations of asthma/wheeze have identified two major immunological phenotypes. The IRF7hi phenotype is characterised by robust upregulation of antiviral response networks, and the IRF7lo phenotype is characterised by upregulation of markers of TGFβ signalling and type 2 inflammation. Similar phenotypes have been identified in infants and children with severe viral bronchiolitis. Notably, genome-wide association studies supported by experimental validation have identified key pathways that increase susceptibility to HRV infection (ORMDL3 and CHDR3) and modulate TGFβ signalling (GSDMB, TGFBR1, and SMAD3). Moreover, functional deficiencies in the activation of type I and III interferon responses are already evident at birth in children at risk of developing febrile lower respiratory tract infections and persistent asthma/wheeze, suggesting that the trajectory to asthma begins at birth or in utero. Finally, exposure to microbes and their products reprograms innate immunity and provides protection from the development of allergies and asthma in children, and therefore microbial products are logical candidates for the primary prevention of asthma. Full article

(This article belongs to the Special Issue Host Infectomics in the Childhood)

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