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.
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.
- Rémi Porte
- Rémi Porte
- Alberto Mantovani
- Rita Silva-Gomes
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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 .
- Evangelos J Giamarellos-Bourboulis, National and Kapodistrian University of Athens, Medical School, Greece
© 2023, Porte et al.
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