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.
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 .
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.
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Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3
eLife 12:e78601.
https://doi.org/10.7554/eLife.78601
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