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The extraordinary expansion of Toxin Antitoxin (TA) modules in the genome of  Mycobacterium tuberculosis  has received significant attention over the last few decades. The cumulative evidence suggests that TA systems are activated in response to stress conditions and are essential for  M. tuberculosis  pathogenesis. In  M. tuberculosis , Rv1955-Rv1956-Rv1957 constitutes the only tripartite TAC ( T oxin  A ntitoxin  C haperone) module. In this locus, Rv1955 (HigB1) encodes for the toxin and Rv1956 (HigA1) encodes for antitoxin. Rv1957 encodes for a SecB-like chaperone that regulates HigBA1 toxin antitoxin system by preventing HigA1 degradation. Here, we have investigated the physiological role of HigB1 toxin in stress adaptation and pathogenesis of  Mycobacterium tuberculosis . qPCR studies revealed that  higBA 1 is upregulated in nutrient limiting conditions and upon exposure to levofloxacin. We also show that the promoter activity of  higBA 1 locus in  M. tuberculosis  is (p)ppGpp dependent. We observed that HigB1 locus is non-essential for  M. tuberculosis  growth under different stress conditions  in vitro . However, guinea pigs infected with  higB 1 deletion strain exhibited significantly reduced bacterial loads and pathological damage in comparison to the animals infected with the parental strain. Transcriptome analysis suggested that deletion of  higB 1 reduced the expression of genes involved in virulence, detoxification and adaptation. The present study describes the role of  higB 1 toxin in  M. tuberculosis  physiology and highlights the importance of  higBA 1 locus during infection in host tissues.

HigB1 Toxin in Mycobacterium tuberculosis Is Upregulated During Stress and Required to Establish Infection in Guinea Pigs