The structure and regulatory circuitry of PrfA are addressed, then antivirulence strategies targeting this protein using natural compounds, synthetic inhibitors, and nanomaterial-based approaches are surveyed.
ABSTRACT Listeria monocytogenes is a gram-positive facultative intracellular bacterium that causes listeriosis in humans and animals. Survival in diverse environments and host-associated niches requires coordinated regulation of metabolism, stress responses, and virulence. The LysR-type transcriptional regulator GltC is predicted to regulate glutamate metabolism, yet its broader contribution to metabolic regulation and pathogenicity in L. monocytogenes remains unclear. Here, we explored the role of GltC in nitrogen utilization, central carbon metabolism, stress tolerance, and virulence. Deletion of gltC had no detectable effect on growth under nutrient-rich, nitrogen-defined conditions or at acidic and alkaline pH, indicating that GltC is not required for basal fitness. Instead, loss of gltC triggered extensive transcriptional remodeling of nitrogen assimilation pathways, including altered expression of genes involved in glutamate synthesis, ammonium transport, and ethanolamine utilization, as well as condition-dependent changes in tricarboxylic acid cycle-associated genes. The ΔgltC mutant exhibited enhanced tolerance to oxidative stress, with improved growth and survival during hydrogen peroxide challenge and increased expression of oxidative stress defense and DNA repair genes. Deletion of gltC led to broad upregulation of the PrfA virulence regulon and a modest increase in hemolytic activity. The ΔgltC strain displayed significantly higher bacterial burdens in the spleen and liver in a murine infection model. Collectively, these results suggest that GltC contributes to the coordination of nitrogen metabolism and oxidative stress adaptation, while influencing bacterial fitness during systemic infection. IMPORTANCE Pathogenic bacteria must constantly balance nutrient acquisition, metabolic activity, and virulence to persist in changing environments. Listeria monocytogenes causes severe foodborne disease and must adapt to changing nutrient and stress conditions during infection. Understanding how metabolism influences virulence is critical for identifying new strategies to limit bacterial survival in the host. This study shows that GltC contributes to the coordination of nitrogen metabolism, oxidative stress adaptation, and bacterial fitness during L. monocytogenes infection. Although GltC is not required for basic growth, its loss alters nitrogen metabolic pathways, enhances oxidative stress tolerance, and is associated with increased bacterial burdens during murine infection. These findings provide new insights into how metabolic regulation influences bacterial adaptation and fitness during host infection. Pathogenic bacteria must constantly balance nutrient acquisition, metabolic activity, and virulence to persist in changing environments. Listeria monocytogenes causes severe foodborne disease and must adapt to changing nutrient and stress conditions during infection. Understanding how metabolism influences virulence is critical for identifying new strategies to limit bacterial survival in the host. This study shows that GltC contributes to the coordination of nitrogen metabolism, oxidative stress adaptation, and bacterial fitness during L. monocytogenes infection. Although GltC is not required for basic growth, its loss alters nitrogen metabolic pathways, enhances oxidative stress tolerance, and is associated with increased bacterial burdens during murine infection. These findings provide new insights into how metabolic regulation influences bacterial adaptation and fitness during host infection.
S. Ogunleye, Monzur Chowdhury, H. Abdelhamed· Microbiology spectrum· 0 citations
ABSTRACT Aspergillus flavus, a ubiquitous filamentous fungus, severely compromises global food safety and public health by producing carcinogenic aflatoxins. Heat shock factor 1 (HSF1) orchestrates stress responses in eukaryotes, yet the functional role and regulatory mechanisms of its homolog, HsfA, in A. flavus remain elusive. Here, we demonstrate that A. flavus encodes two hsfA copies, whose knockdown or expression of a dominant-negative variant abrogates spore germination, a prerequisite for fungal development and colonization. Through integrated reverse genetics, ChIP-qPCR, electrophoretic mobility shift assay, and transcriptional profiling, we identify six non-chaperone targets – brlA, fksP, flbC, sntB, velB, and vosA – directly regulated by HsfA via binding to conserved heat shock elements (HSEs) in their promoters. Ectopic expression of each target partially restores germination, developmental progression, and pathogenicity in HsfA-deficient strains, confirming HsfA’s central role in driving these processes via transcriptional activation. Structural divergence between the A. flavus HsfA DNA-binding domain and human HSF1 explains the ineffectiveness of three HSF1 inhibitors against the fungus. Our findings establish HsfA as a pivotal regulator of A. flavus virulence and uncover a novel HSF regulatory pathway, highlighting HsfA as a promising target for mitigating aflatoxin contamination.
X. Nie, Guolong Zhu, Bei Qin et al.· Virulence· 0 citations
Vector-borne pathogens must adapt to sharply distinct host environments, yet the regulatory logic that coordinates transitions between opposing host-specific programs remains poorly defined. Here, we identify a minimal regulatory module in the flea-borne pathogen
Yersinia pestis
that integrates vector transmission with resistance to mammalian innate immunity. Screening of flea-induced genes uncovered the regulator HdfR, which acts primarily through activation of
maoP
, encoding a nucleoid-associated protein. This HdfR-MaoP module promotes biofilm-dependent foregut blockage in the flea while coordinating baseline envelope adaptations that limit complement recognition and inducible responses that confer resistance to antimicrobial peptides under mammalian host-like conditions. Functional interchangeability of HdfR and MaoP homologs reveals evolutionary conservation of this regulatory logic, and pharmacological perturbation of the module sensitizes
Y. pestis
to antimicrobial peptides. Together, these findings define a parsimonious and evolutionarily conserved regulatory hub that orchestrates bacterial success across abrupt environmental transitions and exposes a tractable point of intervention.
Alexandre Baillez, Amélie Dewitte, F. Pierre et al.· Nature Communications· 0 citations
YgeP plays a central role in APEC pathogenesis by balancing two infection strategies: motility-mediated dissemination and colonization, and biofilm-mediated attachment and tolerance, and negatively regulates key virulence traits during the early stages of infection.
Weiyang Su, Zhe Li, Siqi Feng et al.· Veterinary Microbiology· 0 citations
The Type VI secretion system (T6SS) is a key nanoweapon in Gram-negative bacteria that mediates microbial competition and pathogenesis via toxic effector delivery. Three functionally distinct T6SS clusters (H1-H3) are known in Pseudomonas aeruginosa, yet the broader evolutionary diversity and regulatory networks of T6SS in this pathogen remain poorly defined. Here, we identify Sfa4, a transcriptional regulator linked to a fourth T6SS (H4-T6SS) in clinical isolate LYSZa7. Sfa4 directly binds amrZ and H4-T6SS cluster to activate their transcription. AmrZ, in turn, directly regulates all four T6SS clusters. We further show that c-di-GMP receptor FleQ directly binds the promoters of all four T6SS clusters, revealing a direct regulatory link between c-di-GMP signaling and T6SS transcription. This regulation, together with Sfa4-mediated elevation of intracellular c-di-GMP levels, coordinately enhances H4-T6SS activity, biofilm formation, and virulence in A549 alveolar epithelial cells and Galleria mellonella models. Phylogenetic analysis shows Sfa4 homologs are present in Gram-negative bacteria, implying a potential T6SS-regulatory function. Collectively, our findings shed light on regulatory cascades and provide a mechanistic basis for understanding how clinically acquired T6SS clusters may be integrated into existing virulence networks.
Yizhou Zhang, T. Ye, Jie Deng et al.· International Journal of Bio...· 0 citations
Brucella spp. is a bacterium that can survive under conditions of nutrient starvation and is responsible for foodborne illnesses. The OmpR-type transcriptional regulator is characterized by an N-terminal receiver domain and a C-terminal domain, and it plays a regulatory role in diverse physiological processes, notably nitrogen and carbon metabolism. The genome of Brucella melitensis 16M contains genes for multiple OmpR-family regulators. However, the genetic program associated with nitrogen metabolism remains elusive. Herein, it was demonstrated that the B. melitensis 16M ΔftcR mutant, which lacks the OmpR-type regulator FtcR, displayed compromised viability upon recovery in a nitrogen- and carbon-free medium. Chromatin immunoprecipitation and next-generation sequencing were used to characterize the DNA-binding sites of FtcR. Our genome-wide analysis revealed extensive FtcR-binding sites throughout the B. melitensis 16M genome, including the identification of glnB as a novel target. As glnB encodes a P-II nitrogen regulator, this suggests FtcR plays a direct role in modulating nitrogen, carbon, and energy metabolism under prolonged nutrient starvation. In summary, our findings not only advance our understanding of the transcriptional regulation of nitrogen metabolism but also highlight its critical role in brucellosis pathogenesis, thereby paving the way for the development of novel therapeutics.
Yidan Zhang, Yu Zhang, Shengnan Song et al.· Microorganisms· 0 citations
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