Quorum-sensing regulator LsrR modulates avian pathogenic <i>Escherichia coli</i> pathogenicity through direct regulation of <i>cysN</i>

Avian Pathogenic <i>Escherichia coli</i> (APEC) is a major cause of economic loss in poultry, exacerbated by the rising prevalence of antibiotic resistance. While sulfur metabolism is essential for bacterial growth, its specific role and regulation in APEC virulence remain poorly understood. This study identifies the LsrR-cysN axis as a novel regulatory pathway that critically governs APEC virulence. We demonstrate that the quorum-sensing regulator LsrR directly binds to the <i>cysN</i> promoter, activating its transcription. Functional analysis revealed that <i>cysN</i> deletion drastically attenuated virulence, significantly reducing biofilm formation, serum resistance, adhesion, invasion, and motility. The APEC94∆cysN also exhibited altered antibiotic resistance profiles, which were linked to the upregulation of efflux pumps <i>acrA</i> and <i>tolC</i>. Crucially, in a murine model, the APEC94∆cysN showed a 75% reduction in mortality and severe impairment in colonization of blood, lungs, liver, spleen, and kidneys. This attenuation was associated with a skewed host immune response, characterized by reduced levels of IL-2 and IL-6 and elevated levels of IL-4 and TNF-α. Our findings establish the LsrR-cysN axis as a central regulator connecting quorum sensing to virulence in APEC, revealing a promising target for novel anti-virulence strategies.