Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3
- IRCCS Humanitas Research Hospital, Italy
- University Hospital of Lausanne, Switzerland
- Humanitas University, Italy
- Fondazione Filarete, Italy
- University Fernando Pessoa Canarias, Spain
- Hospital Universitario Virgen del Rocío, Spain
- Complejo Hospitalario Universitario Insular Materno Infantil, Spain
Abstract
Streptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a murine model of invasive pneumococcal infection, PTX3 was strongly induced in non-hematopoietic (particularly, endothelial) cells. The IL-1β/MyD88 axis played a major role in regulation of the Ptx3 gene expression. Ptx3-/- mice presented more severe invasive pneumococcal infection. Although high concentrations of PTX3 had opsonic activity in vitro, no evidence of PTX3-enhanced phagocytosis was obtained in vivo. In contrast, Ptx3-deficient mice showed enhanced recruitment of neutrophils and inflammation. Using P-selectin deficient mice, we found that protection against pneumococcus was dependent upon PTX3-mediated regulation of neutrophil inflammation. In humans, PTX3 genetic polymorphisms were associated with invasive pneumococcal infections. Thus, this fluid phase PRM plays an important role in tuning inflammation and resistance against invasive pneumococcal infection.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file. Source Data files have been provided for Figures 1, 2, 3, 4, 5, 6, 7 and 8 and supplementary figures.
Article and author information
Author details
Funding
Fondazione Cariplo (Contract n{degree sign} 2015-0564)
- Rémi Porte
Fondazione AIRC per la ricerca sul cancro ETS (grant IG-2019 Contract n{degree sign} 23465 and 5x1000 Contract n{degree sign} 21147)
- Rémi Porte
HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA-ESA-ITN,grant number 676129)
- Alberto Mantovani
Fundação para a Ciência e a Tecnologia (PD/BD/114138/2016)
- Rita Silva-Gomes
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece
Ethics
Animal experimentation: Procedures involving animals handling and care were conformed to protocols approved by the Humanitas Clinical and Research Center (Rozzano, Milan, Italy) in compliance with national (4D.L. N.116, G.U., suppl. 40, 18-2-1992 and N. 26, G.U. march 4, 2014) and international law and policies (European Economic Community Council Directive 2010/63/EU, OJ L 276/33, 22.09.2010; National Institutes of Health Guide for the Care and Use of Laboratory Animals, U.S. National Research Council, 2011). All efforts were made to minimize the number of animals used and their suffering. The study was approved by the Italian Ministry of Health (742/2016-PR).
Human subjects: DNA was obtained from 57 pediatric patients with invasive pulmonary disease (IPD) and 521 age- and sex-matched healthy controls from the cohort described by Garcia-Laorden and collaborators (García-Laorden et al., 2020). DNA samples were provided by Carlos Rodriguez-Gallego, Ignacio Obando and Elena Colino .
Version history
- Received: March 13, 2022
- Preprint posted: April 15, 2022 (view preprint)
- Accepted: May 23, 2023
- Accepted Manuscript published: May 24, 2023 (version 1)
- Version of Record published: June 14, 2023 (version 2)
Copyright
© 2023, Porte et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 583
- views
-
- 102
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3
eLife 12:e78601.
https://doi.org/10.7554/eLife.78601
Further reading
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
-
- Genetics and Genomics
- Immunology and Inflammation
Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
