Biology subjects

McGrath-Morrow, S. A.

Publications and source records attributed to McGrath-Morrow, S. A..

3 recordsLinked to original sources

bioRxiv2023

Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in ataxia telangiectasia

Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. MethodsParticipants with stable A-T (n=90) were recruited and compared with unaffected controls (n=15). PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features. ResultsPeople with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4+ T cells and CD8+ T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls. ConclusionUsing an unbiased transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

immunology↗

bioRxiv2022

DNA methyltransferase inhibition induces dynamic gene expression changes in lung CD4+ T cells of neonatal mice with E. coli pneumonia

IntroductionBacterial pulmonary infections are a major cause of morbidity and mortality in neonates, with less severity in older children. Previous studies demonstrated that the DNA of CD4+ T cells in the mouse lung, whose primary responsibility is to coordinate the immune response foreign pathogens, is differentially methylated in neonates compared with juveniles. Nevertheless, the effect of this differential DNA methylation on CD4+ T cell gene expression and response to infection remains unclear. MethodsWe treated E. coli-infected neonatal (4-day-old) and juvenile (13-day-old) mice with decitabine (DAC), a DNA methyltransferase inhibitor with broad-spectrum DNA demethylating activity, and performed simultaneous genome-wide DNA methylation and transcriptional profiling on lung CD4+ T cells. ResultsJuvenile and neonatal mice experienced differential demethylation in response to DAC treatment, with larger methylation differences observed in neonates. By cross-filtering differentially expressed genes between juveniles and neonates with those sites that were demethylated in neonates, we found that interferon-responsive genes such as Ifit1 are the most down-regulated methylation-sensitive genes in neonatal mice. DAC treatment shifted neonatal lung CD4+ T cells toward a gene expression program similar to that of juveniles. ConclusionFollowing lung infection with E. coli, lung CD4+ T cells in neonatal mice exhibit epigenetic repression of important host defense pathways, which are activated by inhibition of DNA methyltransferase activity to resemble a more mature profile.

immunology↗

bioRxiv2022

Cellular and molecular dynamics in the lungs of neonatal and juvenile mice in response to E. coli

Bacterial pneumonias cause significantly higher morbidity and mortality in neonates compared to other age groups. To understand the immune mechanisms that underlie these age-related differences, we employed a mouse model of E. coli pneumonia to examine cellular and molecular dynamics in immune responsiveness in neonates (PND 3-5) and juveniles (PND 12-18) at 24, 48, and 72 hours. Cytokine gene expression from whole lung extracts was quantified using qRT-PCR. E. coli challenge resulted in rapid and significant increases in neutrophils, monocytes, and y{delta}T cells and significant decreases in dendritic cells and alveolar macrophages for both neonates and juveniles. Juveniles had significant increases in interstitial macrophages and recruited monocytes that were not observed in neonatal lungs. Expression of IFN{gamma}-responsive genes were positively correlated with the levels and dynamics of MHCII-expressing innate cells in neonatal and juvenile lungs. Several facets of the responses of wild-type neonates was 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.

immunology↗