A Neonatal Imaging Model of Gram-Negative Bacterial Sepsis

Seman, Brittany G.; Povroznik, Jessica M.; Vance, Jordan K.; Rawson, Travis W.; Robinson, Cory M.

doi:10.3791/61609

Cited by 2 publications

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“…Monocytes (10 5 cells/well) were seeded in a black, clear-bottom 96-well cell culture plate (Eppendorf, Hamburg, Germany) and infected with Escherichia coli O1:K1:H7 that stably expresses luciferase as described previously. 22 Luminescence readings were collected at 2, 4, 8, and 20 h post-gentamicin. Uninfected monocytes served as a negative control for background luminescence signal.…”

Section: Methodsmentioning

confidence: 99%

The impact of opioid exposure during pregnancy on the human neonatal immune profile

et al. 2022

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Background The increasing magnitude of the opioid crisis and rising rates of neonatal abstinence syndrome (NAS) diagnoses highlight the need for increased research into how maternal substance use during pregnancy can impact the neonatal immune profile and its functionality. We hypothesized that neonates with opioid exposure would have reduced proportions of some immune cells, an anti-inflammatory cytokine profile, reduced T cell proliferation, and monocyte bacterial killing activity compared to the control population. Methods The present study compares immune cell populations, inflammatory and anti-inflammatory cytokine and chemokine levels in the serum, and monocyte and T cell functional activity using umbilical cord samples from neonates with known opioid exposure during gestation and from control neonates without known exposure. Results Our findings demonstrated a significant reduction in neutrophils, decreased levels of inflammatory cytokines in the serum, and reduced IL-2 production during in vitro CD4 + T cell proliferation in neonates exposed to opioids compared to controls. The neutrophil findings were supported by retrospective analysis of an extended network of deidentified patient records. Conclusions This study is the first of its kind to evaluate differences in neonatal immunity as a result of opioid exposure in the human population that will inform continued mechanistic studies. Impact The opioid epidemic has become a public health crisis in the United States, and the corresponding incidence of neonatal abstinence syndrome (NAS) have risen accordingly. New research is required to understand the short and long-term health impacts of opioid exposure to the neonate. This is the first human study to investigate the immunologic profile and functionality in neonates with known opioid exposure in utero. The abundance of neutrophils and the ratio of neutrophils to lymphocytes is significantly reduced along with inflammatory cytokines and chemokines following opioid exposure during pregnancy. The immune profile in opioid-exposed neonates may promote susceptibility to infection.

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Section: Methodsmentioning

confidence: 99%

The impact of opioid exposure during pregnancy on the human neonatal immune profile

et al. 2022

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“…Escherichia coli strain O1:K1:H7 was obtained from the ATCC (Manassis, VA) and grown in Luria broth from a single colony isolated on Tryptic Soy agar (TSA). To prepare infectious inoculums, the bacteria were enumerated as described previously ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

“…Neonatal pups (n=3 per group (control vs. infected) per genotype (WT vs . KO)) at 4 days were inoculated subcutaneously in the scapular region with E. coli O1:K1:H7 using a 28-gauge insulin needle as described previously ( 20 , 21 ). The bacteria were washed with PBS, centrifuged at 2,000 x g for 5 min, and suspended in a volume of PBS equivalent to an inoculum of 50 μL/mouse.…”

Section: Methodsmentioning

confidence: 99%

“…Beyond the emergent situation that sepsis represents in the neonate, the condition further predisposes to secondary infections and poor neurodevelopmental outcomes ( 17 , 19 ). Recently, we established a murine neonatal model of Escherichia coli O1:K1:H7-induced sepsis to explore the impact of early life IL-27 levels on the host response to infection ( 20 , 21 ). In this model, neonatal pups deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of the bacterial burden with reduced systemic inflammation ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-27-dependent transcriptome signatures during neonatal sepsis

et al. 2023

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Human newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells and tissues from mice and humans. In a murine model of neonatal sepsis, mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of bacteria with reduced systemic inflammation. To explore a reprogramming of the host response in the absence of IL-27 signaling, we profiled the transcriptome of the neonatal spleen during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. We identified 634 genes that were differentially expressed, and those most upregulated in WT mice were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. These genes failed to increase in the IL-27Rα KO mice. We further isolated an innate myeloid population enriched in macrophages from the spleens of control and infected WT neonates and observed similar changes in gene expression aligned with changes in chromatin accessibility. This supports macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight the first report of improved pathogen clearance amidst a less inflammatory environment in IL-27Rα KO. This suggests a direct relationship between IL-27 signaling and bacterial killing. An improved response to infection that is not reliant upon heightened levels of inflammation offers new promise to the potential of antagonizing IL-27 as a host-directed therapy for neonates.

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A Neonatal Imaging Model of Gram-Negative Bacterial Sepsis

Cited by 2 publications

References 0 publications

The impact of opioid exposure during pregnancy on the human neonatal immune profile

The impact of opioid exposure during pregnancy on the human neonatal immune profile

Interleukin-27-dependent transcriptome signatures during neonatal sepsis

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