CodY Is a Global Transcriptional Regulator Required for Virulence in Group B Streptococcus

Abstract

Group B Streptococcus (GBS) is a Gram-positive bacterium able to switch from a harmless commensal of healthy adults to a pathogen responsible for invasive infections in neonates. The signals and regulatory mechanisms governing this transition are still largely unknown. CodY is a highly conserved global transcriptional regulator that links nutrient availability to the regulation of major metabolic and virulence pathways in low-G+C Gram-positive bacteria. In this work, we investigated the role of CodY in BM110, a GBS strain representative of a hypervirulent lineage associated with the majority of neonatal meningitis. Deletion of codY resulted in a reduced ability of the mutant strain to cause infections in neonatal and adult animal models. The observed decreased in vivo lethality was associated with an impaired ability of the mutant to persist in the blood, spread to distant organs, and cross the blood-brain barrier. Notably, the codY null mutant showed reduced adhesion to monolayers of human epithelial cells in vitro and an increased ability to form biofilms, a phenotype associated with strains able to asymptomatically colonize the host. RNA-seq analysis showed that CodY controls about 13% of the genome of GBS, acting mainly as a repressor of genes involved in amino acid transport and metabolism and encoding surface anchored proteins, including the virulence factor Srr2. CodY activity was shown to be dependent on the availability of branched-chain amino acids, which are the universal cofactors of this regulator. These results highlight a key role for CodY in the control of GBS virulence.

Deletion of codY impairs Staphylococcus epidermidis biofilm formation, generation of viable but non-culturable cells and stimulates cytokine production in human macrophages

“…CodY has been reported as a global transcriptional regulator that predominantly represses the expression of hundreds of genes in different bacterial species under adverse conditions [13]. To date, aside from our initial study highlighting increased codY expression in S. epidermidis biofilms grown under VBNC conditions [14], which suggests its role in the formation of VBNC cells, no other studies have been reported on S. epidermidis regarding the role of codY .…”

“…CodY, a global regulator that has been associated with biofilm phenotype in several bacterial species [10–13], was among the proteins showing high reactivity to human serum when cells were grown under VBNC-inducing conditions [9]. Recently, our group demonstrated that codY expression was upregulated in biofilms with higher proportions of VBNC cells [14], substantiating the potential involvement of this global regulator in S. epidermidis virulence.…”

Oligonucleotide Library Assisted Sequence Mining Reveals Promoter Sequences With Distinct Temporal Expression Dynamics For Applications InCurvibactersp. AEP1-3

“…The only motif found in this 5’UTR is similar to TF-Motifs found in Gram-positive bacteria, the motif is located within the positions 20 - 29 (TTACAAGAAA) of the 5’UTR. Specifically, similar to motifs of the global transcriptional regulator CodY from Lactococcus lactis and Streptococcus pyogenes as well as for CcpA from Streptococcus pneumoniae (s. Figure 3 - 5 and Supplementary Table 3) [28, 29, 30, 31].…”

“…Those transcriptional regulators are known to regulate the expression of a wide range of genes, e.g. genes responsible for carbohydrate and (p)ppGpp metabolism or virulence factors [29, 30, 31]. Regarding the expression of the reporter driven by CPL0025 and the previous finding that the promoter region of Curl2 is activated by AHLs, it is possible that the motif responsible for AHL induction is located within the 76 bp long 5’UTR of CPL0025.…”

Genomic Evidence for Extra-Intestinal Foodborne Disease due to Zoonotic Bacteria: A Public Health Risk

“…GBS is among the leading cause of meningitis in newborns who inhale or ingest amniotic fluid before or during delivery (Fischer et al, 2021). Of the ten known GBS capsular serotypes, six (Ia, Ib, II, III, IV, and V) are the most frequent serotypes associated with invasive disease and the clone GBS III/ST17, associated with GBS meningitis (Pellegrini et al, 2022). Kayansamruaj et al (2019).…”