Brucella abortus transcriptional regulator ArsR6 inhibits host pyroptosis via BAB_RS28760 by triggering the endoplasmic reticulum stress pathway

Abstract

Pyroptosis, which is accompanied by inflammatory responses, is critical for pathogen clearance. However, the mechanism through which Brucella evades host pyroptosis remains unclear. The transcriptional regulator ArsR6 maintains bacterial intracellular homeostasis and possibly influences host cell death. However, whether ArsR6 acts on cellular pyroptosis is unknown. Therefore, we investigated pathogen-host interactions within macrophages infected with Brucella abortus (B. abortus), and found that ArsR6 is crucial for inhibiting host cell pyroptosis after B. abortus infection. The downstream target gene, BAB_RS28760 of ArsR6 was screened using chromatin immunoprecipitation sequencing. BAB_RS28760 belongs to the BA14K protein family and is strongly immunoreactive and induces humoral and cellular immune responses in the host during infection. Deleting ArsR6 in B. abortus promotes pyroptosis and enhancs the intracellular survival of B. abortus. In addition, ArsR6 negatively regulated its target gene BAB_RS28760, whereas BAB_RS28760 deletion downregulated cellular pyroptosis by inhibiting endoplasmic reticulum stress and decreasing the intracellular survival of B. abortus. Our results reveal for the first time that Brucella ArsR6 reduces endoplasmic reticulum stress activation by negatively regulating its downstream target genes, thus inhibiting host cell pyroptosis. Our study provides new insights into the pathogenic mechanisms of Brucella, which can provide potential selectivity for the development of anti-Brucella therapies.