TcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection.
Miljan StuparLendl TanEdward D KerrChristopher J De VossBrian M FordeBenjamin L SchulzNicholas P WestPublished in: Nature communications (2024)
The ability of Mycobacterium tuberculosis (Mtb) to persist in the host complicates and prolongs tuberculosis (TB) patient chemotherapy. Here we demonstrate that a neglected two-component system (TCS) of Mtb, TcrXY, is an autoregulated acid-sensing TCS that controls a functionally diverse 70-gene regulon required for bacterial persistence. Characterisation of two representatives of this regulon, Rv3706c and Rv3705A, implicate these genes as key determinants for the survival of Mtb in vivo by serving as important effectors to mitigate redox stress at acidic pH. We show that genetic silencing of the response regulator tcrX using CRISPR interference attenuates the persistence of Mtb during chronic mouse infection and improves treatment with the two front-line anti-TB drugs, rifampicin and isoniazid. We propose that targeting TcrXY signal transduction blocks the ability of Mtb to sense and respond to acid stress, resulting in a disordered program of persistence to render the organism vulnerable to existing TB chemotherapy.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- genome wide
- transcription factor
- locally advanced
- copy number
- dna methylation
- gene expression
- genome wide identification
- case report
- squamous cell carcinoma
- crispr cas
- emergency department
- human immunodeficiency virus
- radiation therapy
- rectal cancer
- hepatitis c virus
- chemotherapy induced
- type iii
- antiretroviral therapy
- hiv infected
- electron transfer