Cellular and molecular dynamics in the lungs of neonatal and juvenile mice in response to E. coli
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eLife assessment
This study examines the inflammatory and immune response to live E. coli bacterial infection in neonatal and juvenile mice. Important information is described on the roles of Class II MHC and interferon responsive genes in regulating the host response to infection. This study will inform future efforts to further elucidate the impact of bacterial infections on lung development.
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Abstract
Bacterial pneumonia in neonates can cause significant morbidity and mortality when compared to other childhood age groups. To understand the immune mechanisms that underlie these age-related differences, we employed a mouse model of Escherichia coli pneumonia to determine the dynamic cellular and molecular differences in immune responsiveness between neonates (PND 3–5) and juveniles (PND 12–18), at 24, 48, and 72 hr. Cytokine gene expression from whole lung extracts was also quantified at these time points, using quantitative RT-PCR. E. coli challenge resulted in rapid and significant increases in neutrophils, monocytes, and γδT cells, along with significant decreases in dendritic cells and alveolar macrophages in the lungs of both neonates and juveniles. E. coli -challenged juvenile lung had significant increases in interstitial macrophages and recruited monocytes that were not observed in neonatal lungs. Expression of IFNγ-responsive genes was positively correlated with the levels and dynamics of MHCII-expressing innate cells in neonatal and juvenile lungs. Several facets of immune responsiveness in the wild-type neonates were recapitulated in juvenile MHCII −/− juveniles. Employing a pre-clinical model of E. coli pneumonia, we identified significant differences in the early cellular and molecular dynamics in the lungs that likely contribute to the elevated susceptibility of neonates to bacterial pneumonia and could represent targets for intervention to improve respiratory outcomes and survivability of neonates.
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eLife assessment
This study examines the inflammatory and immune response to live E. coli bacterial infection in neonatal and juvenile mice. Important information is described on the roles of Class II MHC and interferon responsive genes in regulating the host response to infection. This study will inform future efforts to further elucidate the impact of bacterial infections on lung development.
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Reviewer #1 (Public Review):
The authors use a model of neonatal E.coli pneumonia to study differences between early neonates ad juvenile animals. They observe increased monocyte derived macrophage recruitment in juveniles compared to neonates as well as an increase in IFNG related genes. The data are of potential interest but in its current form it is unclear how well the experiments were controlled for confounders, such as sex and CFU.
1. This paper conducted research to identify the window of susceptibility to pneumonia due to E. coli, a bacteria that most often causes pneumonia in the neonatal period. This is an understudied area and thus the research is significant.
2. The paper provides evidence of differences in immune response in neonatal mice vs juvenile mice. However, it is unclear if the data are controlled adequately for the …
Reviewer #1 (Public Review):
The authors use a model of neonatal E.coli pneumonia to study differences between early neonates ad juvenile animals. They observe increased monocyte derived macrophage recruitment in juveniles compared to neonates as well as an increase in IFNG related genes. The data are of potential interest but in its current form it is unclear how well the experiments were controlled for confounders, such as sex and CFU.
1. This paper conducted research to identify the window of susceptibility to pneumonia due to E. coli, a bacteria that most often causes pneumonia in the neonatal period. This is an understudied area and thus the research is significant.
2. The paper provides evidence of differences in immune response in neonatal mice vs juvenile mice. However, it is unclear if the data are controlled adequately for the bacterial burden in the lung, which would be a crucial control to control for epi-phenomena. Additionally, it is unclear if the molecules that regulate macrophage recruitment are defective in neonatal mice or if it is an issue of macrophage progenitor cells.
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Reviewer #2 (Public Review):
The authors have provided important detailed information on the inflammatory response to live E. coli infection in neonatal and juvenile mouse lungs. They have delineated key distinctions in these two periods and the potential impact on lung development. The study will inform future lines of investigation on the impact of bacterial infections on lung development.
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