Neonates have increased vulnerability to life-threatening infections due to the distinct immune landscape. Interleukin (IL)-27 is a key component of this immune profile that we have previously shown t Show more
Neonates have increased vulnerability to life-threatening infections due to the distinct immune landscape. Interleukin (IL)-27 is a key component of this immune profile that we have previously shown to be elevated in both newborn humans and mice. IL-27 continues to increase in the serum and tissues consistent with poor outcomes during gram-negative neonatal bacterial sepsis. Presently, we dissected the IL-27 producer profile at a single-cell level using IL-27p28eGFP reporter mice in our previously established model of neonatal sepsis with luciferase-expressing K1-encapsulated Escherichia coli. Whole animal imaging regionally highlighted the spleen, liver, and lungs as key infection sites by bacterial luminescence. Flow cytometry showed that IL-27 producers increased significantly in the liver with infection and were predominantly F4/80+ and CD11b+ with subpopulations that emerged expressing additional markers. This information paired with single-cell RNA sequencing further identified the most robust populations as monocytes, monocyte-derived cells, and Kupffer cells followed by smaller populations of dendritic cells and neutrophils. The transcriptome demonstrated a diverse range of functionality amongst populations that included differential expression of genes implicated in bactericidal, metabolic, and inflammatory changes. Collectively, the transcriptome of IL-27 producers from the livers of infected animals suggests an uncoordinated mix of inflammatory and suppressive activity that may contribute to immune dysregulation characteristic of sepsis. Together, this work provides previously undescribed insight into the details of IL-27 producers during early-life infection. This further provides essential information needed to support IL-27 as a therapeutic target for neonatal bacterial sepsis. Show less
Neonates are at an increased risk of an infectious disease. This is consistent with an increased abundance of myeloid-derived suppressor cells (MDSCs) compared with older children and adults. Using a Show more
Neonates are at an increased risk of an infectious disease. This is consistent with an increased abundance of myeloid-derived suppressor cells (MDSCs) compared with older children and adults. Using a murine model of neonatal bacterial sepsis, we demonstrate that MDSCs modulate their activity during an infection to enhance immune suppressive functions. A gene expression analysis shows that MDSCs increased NOS2, Arg-1 and IL-27p28 expression in vitro and in vivo in response to Show less
CPSI deficiency usually results in severe hyperammonemia presenting in the first days of life warranting prompt diagnosis. Most CPS1 defects are non-recurrent, private mutations, including point mutat Show more
CPSI deficiency usually results in severe hyperammonemia presenting in the first days of life warranting prompt diagnosis. Most CPS1 defects are non-recurrent, private mutations, including point mutation, small insertions and deletions. In this study, we report the detection of large deletions varying from 1.4 kb to >130 kb in the CPS1 gene of 4 unrelated patients by targeted array CGH. These results underscore the importance of analysis of large deletions when only one mutation or no mutations are identified in cases where CPSI deficiency is strongly indicated. Show less