RV3295 (LuxR1) Is a Transcriptional Regulator Important for Virulence in the Mycobacterium Tuberculosis and Mycobacterium Marinum In Vitro and In Vivo Models

Abstract

Mycobacterium tuberculosis (Mtb) is the infectious agent that causes tuberculosis (Tb). In 2014, 1.5 million people succumbed to tuberculosis while an additional nine million became infected. Tuberculosis is a worldwide problem, since one in three are currently infected. Symptoms of active disease include a persistent cough, malaise, weight loss, fever, and night sweats. Treatment lasts an average of six months of combination antibiotic therapy. There is a Tb vaccine, but vaccination efficacy can vary from 0-80%. Therefore, there is an urgent need to study and better understand Mtb pathogenesis.

Mtb is a slow growing organism, and it is difficult to manipulate genetically. Genetic regulation of virulence mechanisms are still being elucidated in Mtb. LuxR proteins are master regulators that have conserved functions in many pathogenic bacteria. Rv3295 (LuxR1) is a putative LuxR homologue present in Mtb and has close homologues only in pathogenic mycobacterial species. luxR1 is necessary for robust replication in macrophages in both Mtb and Mycobacterium marinum (Mm). In Mtb infections, the luxR1 mutant is not able to thrive as well the wild type in the lungs but disseminated more rapidly to the spleen and liver. In Mm infections, the luxR1 mutant is attenuated in a footpad model. Transcriptional profiling of the wild type and the luxR1 mutant at early log or early stationary growth phase suggest luxR1 regulates dormancy and the stringent response. Transcriptional analysis in Mm supports the transcriptional data obtained with Mtb. Collectively, these data support a role for luxR1 regulating the adaptive response of mycobacteria to different environments and suggest the potential involvement of this gene in establishment or reactivation from latency.