A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4

Alsina, Laia; Israelsson, Elisabeth; Altman, Matthew C.; Dang, Kristen K.; Ghandil, Pegah; Israël, Laura; Bernuth, Horst von; Baldwin, Nicole; Qin, Haili; Jin, Zongbo; Banchereau, Romain; Anguiano, Esperanza; Ionan, Alexei; Abel, Laurent; Puel, Anne; Pïcard, Capucine; Pascual, Virginia; Casanova, Jean‐Laurent; Chaussabel, Damien

doi:10.1038/ni.3028

Cited by 81 publications

(94 citation statements)

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“…It seems intriguing that monocytes as circulating MF progenitors do not require TLR13 or UNC-93B and, hence, endosomal TLR signaling altogether, for a potent cytokine response to streptococci and staphylococci. In line with this data, a recent study of patients deficient in MyD88/IRAK4 demonstrated a residual responsiveness of blood cells to whole heat-killed bacteria, in contrast to the complete loss of response to purified bacterial TLR ligands (43). In this context, the discrete role of MyD88 in circulating myeloid cell subsets in response to GBS remains to be established.…”

Section: Discussionmentioning

confidence: 63%

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

Kolter

Feuerstein

Spoeri

et al. 2016

The Journal of Immunology

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International audienceStreptococci are common human colonizers with a species-specific mucocutaneous distribution. At the same time, they are among the most important and most virulent invasive bacterial pathogens. Thus, site-specific cellular innate immunity, which is predominantly executed by resident and invading myeloid cells, has to be adapted with respect to streptococcal sensing, handling, and response. In this article, we show that TLR13 is the critical mouse macrophage (MΦ) receptor in the response to group B Streptococcus, both in bone marrow-derived MΦs and in mature tissue MΦs, such as those residing in the lamina propria of the colon and the dermis, as well as in microglia. In contrast, TLR13 and its chaperone UNC-93B are dispensable for a potent cytokine response of blood monocytes to group B Streptococcus, although monocytes serve as the key progenitors of intestinal and dermal MΦs. Furthermore, a specific role for TLR13 with respect to MΦ function is supported by the response to staphylococci, where TLR13 and UNC-93B limit the cytokine response in bone marrow-derived MΦs and microglia, but not in dermal MΦs. In summary, TLR13 is a critical and site-specific receptor in the single MΦ response to β-hemolytic streptococci

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Section: Discussionmentioning

confidence: 63%

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

Kolter

Feuerstein

Spoeri

et al. 2016

The Journal of Immunology

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“…Chaussabel et al (Chaussabel et al, 2008) developed a strategy for blood microarray data analysis which identified genes co-expressed across multiple disease datasets and classified them into 28 blood transcriptional modules. The genes belonging to such functionally related clusters can be used to generate a disease-specific transcription signature which may serve for diagnostics or treatment prognosis (Berry et al, 2010). In another approach, 334 blood transcriptional modules (BTMs) were annotated according to biological function or tissue-specific expression by Li et al (Li et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…In order to generate feature sets based on gene co-expression, several studies have attempted to determine meaningful relationships between genes based on their regulation; by measuring changes in gene expression under various environmental conditions in distinct organisms they have provided models for the discovery of transcriptional modules (Bar-Joseph et al, 2003;Liu et al, 2007), resulting in a broad range of gene classification collections. Chaussabel et al (Chaussabel et al, 2008) developed a strategy for blood microarray data analysis which identified genes co-expressed across multiple disease datasets and classified them into 28 blood transcriptional modules.…”

Section: Introductionmentioning

confidence: 99%

“…For example, there have been efforts to characterize functional associations between genes or metabolites on the basis of common patterns of their regulation in response to environmental challenges (Berry et al, 2010;Pascual, Chaussabel & Banchereau, 2010). These annotated "feature sets" equip biologists with a powerful method for predicting programs activated by an organism in response to a given stimulus, whereby novel data sets can be elucidated by detecting enrichments of previously described feature sets.…”

Section: Introductionmentioning

confidence: 99%

“…BTMs have proved successful in immunological applications, e.g. for autoimmune diseases (Pascual, Chaussabel & tmod: an R package for general and multivariate enrichment analysis or predicting response to pyogenic bacteria in patients carrying mutations in pathways responsible for pathogen sensing (Alsina et al, 2014). Other widely used gene collections useful for interpretation of transcriptome data sets include annotated gene sets used with GSEA (Gene Set Enrichment Analysis) software available in the MSigDB database (Subramanian et al, 2005), gene ontology (GO) annotations, and pathway annotations such as KEGG pathways.…”

Section: Introductionmentioning

confidence: 99%

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tmod: an R package for general and multivariate enrichment analysis

Weiner

Domaszewska

2016

Preprint

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ABSTRACT"Omics" studies generate long lists of genes, proteins, metabolites or other features which can be difficult to decipher. Feature set enrichment analysis utilizing annotated groups/classes of features (such as pathways, gene ontology terms or gene/metabolic modules) can provide a powerful gateway to associate data to phenotypes such as disease process or treatment progression. At the same time, the increasing use of technologies to generate multidimensional omics data sets based on specific cell types or responses to stimuli increases the number and breadth of annotated feature sets available for enrichment analysis, facilitating the ability to draw biologically relevant conclusions. However, existing tools and applications for enrichment analysis are adapted specifically to gene set enrichment and lack functionalities to analyze rapidly growing amounts of metabolomics and other data. Moreover, such tools often provide only a limited range of statistical methods, rely on permutation tests, lack suitable visualization tools to facilitate result interpretation in complex experimental setups, and lack standalone versions usable in semi-automatized workflows. Here, we present tmod, an R package which implements powerful statistical methods for enrichment analysis. Tmod includes definitions of widely used feature sets for transcriptomic and metabolomic profiling and also allows use of custom user-provided feature sets. Moreover, it provides novel and intuitive visualization methods which facilitate interpretation of complex data sets. The implemented statistical tests allow the significance of enrichment within sorted feature lists to be calculated without randomization tests and thus are suitable for combining functional analysis with multivariate techniques.

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Human dendritic cells activated with MV130 induce Th1, Th17 and IL‐10 responses via RIPK2 and MyD88 signalling pathways

et al. 2017

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Recurrent respiratory tract infections (RRTIs) are the first leading cause of community‐ and nosocomial‐acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat‐inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown. Herein, we study the capacity of MV130 to immunomodulate the function of human dendritic cells (DCs) as a potential mechanism that contribute to the clinical benefits. We demonstrate that DCs from RRTIs patients and healthy controls display similar ex vivo immunological responses to MV130. By combining systems biology and functional immunological approaches we show that MV130 promotes the generation of Th1/Th17 responses via receptor‐interacting serine/threonine‐protein kinase‐2 (RIPK2)‐ and myeloid‐differentiation primary‐response gene‐88 (MyD88)‐mediated signalling pathways under the control of IL‐10. In vivo BALB/c mice sublingually immunized with MV130 display potent systemic Th1/Th17 and IL‐10 responses against related and unrelated antigens. We elucidate immunological mechanisms underlying the potential way of action of MV130, which might help to design alternative treatments in other clinical conditions with high risk of recurrent infections.

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A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4

Cited by 81 publications

References 50 publications

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

tmod: an R package for general and multivariate enrichment analysis

Human dendritic cells activated with MV130 induce Th1, Th17 and IL‐10 responses via RIPK2 and MyD88 signalling pathways

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