Regulation of inflammation and protection against invasive pneumococcal infection by the long pentraxin PTX3
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Curated by eLife
Evaluation Summary:
This submission represents a holistic approach to how pentraxin 3 (PTX3) modulates susceptibility to experimental infection by Streptococcus pneumoniae. The authors have built robust findings on the importance of PTX3 for the survival of mice and they have extensively investigated all different aspects of the mechanism of PTX3 protection. One main strength of the manuscript is its usage of bone marrow chimeras in addition to total as well as tissue-specific mouse strains that support their claims.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Abstract
Streptococcus pneumoniae is a major pathogen in children, elderly subjects, and immunodeficient patients. Pentraxin 3 (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 gene 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.
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Evaluation Summary:
This submission represents a holistic approach to how pentraxin 3 (PTX3) modulates susceptibility to experimental infection by Streptococcus pneumoniae. The authors have built robust findings on the importance of PTX3 for the survival of mice and they have extensively investigated all different aspects of the mechanism of PTX3 protection. One main strength of the manuscript is its usage of bone marrow chimeras in addition to total as well as tissue-specific mouse strains that support their claims.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In their manuscript, Porte et al. investigate the role of Pentraxin 3 in S.pneumoniae infection. The authors provide a series of experiments in which they show that PTX3 is induced systemically and locally after S.pneumonieae infection in a time-dependent manner and its correlation with IL-1b levels in the lung. Using Ptx3 k.o. animal, the authors provide evidence that this gene confers resistance to infection. Further, it is convincingly shown that PTX3 in pneumococcus infection is derived from non-hematopoietic cells and predominantly the endothelial compartment and regulates neutrophil-mediated inflammation. This is a very elegant and complete manuscript that is a joy to read.
I want to highlight the main strength of the manuscript, which is its the usage of bone marrow chimeras in addition to total as …
Reviewer #1 (Public Review):
In their manuscript, Porte et al. investigate the role of Pentraxin 3 in S.pneumoniae infection. The authors provide a series of experiments in which they show that PTX3 is induced systemically and locally after S.pneumonieae infection in a time-dependent manner and its correlation with IL-1b levels in the lung. Using Ptx3 k.o. animal, the authors provide evidence that this gene confers resistance to infection. Further, it is convincingly shown that PTX3 in pneumococcus infection is derived from non-hematopoietic cells and predominantly the endothelial compartment and regulates neutrophil-mediated inflammation. This is a very elegant and complete manuscript that is a joy to read.
I want to highlight the main strength of the manuscript, which is its the usage of bone marrow chimeras in addition to total as well as tissue specific mouse strains that support their claims.
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Reviewer #2 (Public Review):
This study by Porte et al examines the role of the soluble pattern recognition molecule long pentraxin 3 (PTX3) in host defense against S. pneumoniae. They find that PTX3 is required for control of bacterial numbers in the lungs, systemic dissemination and host survival following infection with S. pneumoniae serotype 3, a strain of public concern. They further confirm findings with other pneumococcal serotypes and find that PTX3 can protect the host if administered as a treatment post infection. In exploring mechanisms of protection, they find that pneumococcal infection upregulates PTX3 expression in a Myd88/ IL-1 dependent manner and that endothelial cells are a primary source of PTX3. They convincingly show that PTX3 control of bacterial numbers is not due to enhancement of neutrophil antimicrobial …
Reviewer #2 (Public Review):
This study by Porte et al examines the role of the soluble pattern recognition molecule long pentraxin 3 (PTX3) in host defense against S. pneumoniae. They find that PTX3 is required for control of bacterial numbers in the lungs, systemic dissemination and host survival following infection with S. pneumoniae serotype 3, a strain of public concern. They further confirm findings with other pneumococcal serotypes and find that PTX3 can protect the host if administered as a treatment post infection. In exploring mechanisms of protection, they find that pneumococcal infection upregulates PTX3 expression in a Myd88/ IL-1 dependent manner and that endothelial cells are a primary source of PTX3. They convincingly show that PTX3 control of bacterial numbers is not due to enhancement of neutrophil antimicrobial activity but rather due to control of pulmonary inflammation. They find that absence of PTX3 was linked to pulmonary damage driven by increased PMN influx. They find that PTX3 is required for control of pulmonary PMN recruitment, likely acting at the PMN trans-endothelial migration step by controlling P-selectin mediated migration. Importantly, they identify two SNPs in PTX3 are associated increased risk of invasive pneumococcal disease. This study is of high clinical relevance and provides important contributions to the field in terms of understanding regulators of pulmonary inflammation in bacterial pneumonia. The experiments are very well controlled and the manuscript is easy to follow.
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