Biomedical subjects

Jennifer A Gaddy

Publications and source records attributed to Jennifer A Gaddy.

3 recordsLinked to original sources

PubMed2026

Human Milk Oligosaccharides Modulate Nitrogen Utilization in Lactobacillus crispatus in a Glucose-Dependent Manner.

The vaginal microbiome's transition to a dysbiotic state increases susceptibility to pathogens like group B Streptococcus. While human milk oligosaccharides are established prebiotics in the neonatal gut, their impact on the vaginal niche remains largely unexplored. This study investigated the effects of pooled human milk oligosaccharides on the growth and physiology of vaginal (Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners) and gut-derived (Lactobacillus reuteri, Lactobacillus rhamnosus) commensals. Growth analyses revealed that human milk oligosaccharides significantly and selectively stimulated growth across all vaginal strains tested, whereas gut commensals exhibited variable or inhibited growth. Carbohydrate utilization assays and comparative genomics against Bifidobacterium infantis showed that Lactobacillus crispatus and Lactobacillus reuteri lack the canonical metabolic machinery to catabolize human milk oligosaccharides. Instead, nitrogen utilization assays identified a glucose-dependent pathway where human milk oligosaccharides are associated with the depletion of primary amines and amino acids in Lactobacillus crispatus supernatants. These results suggest that human milk oligosaccharides act as noncatabolic modulators of vaginal lactobacilli. Collectively, these in vitro findings may warrant investigation of human milk oligosaccharides as modulators of vaginal commensal physiology in more complex experimental systems.

Humans↗

PubMed2026

SpxA1 and SpxA2 function as a stoichiometry-dependent regulatory rheostat governing virulence gene expression in group A Streptococcus.

UNLABELLED: Group A Streptococcus (GAS) is a human-restricted pathogen whose global incidence has surged in the post-COVID era. The ability of GAS to shift from a colonizing to invasive phenotype depends on coordinated virulence gene regulation in response to host-derived signals. However, the mechanisms by which individual stress-sensing systems interact to reshape the virulence gene regulatory landscape remain incompletely understood. Here, we define the regulatory programs of two conserved transcriptional regulator paralogs, SpxA1 and SpxA2, using an integrated multi-omic approach combining RNA-seq, data-independent acquisition proteomics, NanoString-based transcriptional profiling across multiple host-relevant stress conditions, and chromatin immunoprecipitation with exonuclease treatment (ChIP-exo). RNA-seq revealed functionally distinct regulons with SpxA1 governing oxidative stress defense and SpxA2 coordinating virulence-associated gene expression linked to the CovRS two-component regulatory system. Proteomic analysis established SpxA2 as a ClpXP protease substrate in GAS and identified reciprocal paralog accumulation upon loss of either SpxA1 or SpxA2, consistent with compensatory transcriptional upregulation. NanoString profiling under bacitracin and human neutrophil peptide-1 challenge identified four gene modules with distinct stoichiometry-dependent and condition-dependent regulatory logic, revealing that the SpxA1/SpxA2 ratio rather than the activity of either paralog alone determines which transcriptional programs are engaged. ChIP-exo demonstrated that SpxA2 directly modulates CovR-DNA binding occupancy in a CovR-binding motif-dependent manner, simultaneously antagonizing CovR dimer binding at an extended (25 bp) CovR motif and facilitating CovR monomer binding at the canonical ATTARA motif. These findings establish the LiaFSR-SpxA2-CovRS axis as a cross-regulatory circuit through which GAS cell envelope stress sensing is directly transduced into coordinated virulence gene regulatory changes. IMPORTANCE: Group A Streptococcus (GAS) causes millions of infections annually, including a recent global surge in invasive disease. To survive in the human host, GAS must rapidly reprogram virulence gene expression in response to host-derived stresses. This study characterizes two conserved transcriptional regulators, SpxA1 and SpxA2, that govern this response through interaction with RNA polymerase to indirectly influence the DNA-binding activity of downstream transcription factors. We show that SpxA2, activated by a cell envelope stress-sensing system responding to human antimicrobial peptides, reshapes the binding of the master virulence regulator CovR in a promoter-specific manner, coupling cell envelope stress sensing to virulence gene regulation. The stoichiometric balance between SpxA1 and SpxA2 functions as a regulatory rheostat calibrating overall virulence gene regulatory tone, providing a framework for understanding how RNA polymerase-interacting regulators coordinate stress responses and virulence gene control across Gram-positive bacterial pathogens.

Streptococcus pyogenes↗

PubMed2025

Genomic adaptation in group B Streptococcus following intrapartum antibiotic prophylaxis and childbirth.

Through vaginal colonization, GBS causes severe outcomes including neonatal sepsis and meningitis. Although intrapartum antibiotic prophylaxis (IAP) has reduced neonatal disease rates, persistent GBS colonization has been observed in patients following prophylaxis. To determine whether IAP selects for genomic signatures that enhance GBS survival and persistence, a pangenome analysis was performed on 97 isolates from 58 participants before (prenatal) and after (postpartum) IAP/childbirth. Thirty-one of the 34 paired strains from participants with persistent colonization clustered together in the core gene phylogeny, suggesting that the strains recovered at the postpartum sampling were highly similar to those recovered at the prenatal visit. A core-gene mutation analysis identified mutations in 74% (n=23) of the 31 postpartum genomes when compared to the prenatal strains of the same multilocus sequence type recovered from the same individuals. Several strains had acquired mutations in the same colonization-associated genes, though two postpartum strains accounted for most of the mutations. These two outliers were classified as mutators based on high mutation rates and mutations within DNA repair system genes. Increased biofilm production was observed in half of the postpartum strains relative to the prenatal strains, which is supported by the presence of point mutations in genes associated with adherence. Together, these findings suggest that antibiotics may impose a selective pressure on GBS that selects for mutations and phenotypes that promote adaptation and survival in vivo. Enhanced survival in the genitourinary tract can lead to persistent colonization, increasing the likelihood of invasive disease in subsequent pregnancies and in newborns following IAP.

Journal Article↗