Ability of mycobacterial pathogens to establish a persistent infection is lost by deletion of a single gene, rel, regulator of the stringent response

Studies in a mouse model revealed Mycobacterium tuberculosis (Mtb) with a deletion of rel, regulator of the stringent response, could not establish a persistent infection. Follow up studies in cattle with a Mycobacterium. a. paratuberculosis rel deletion mutant revealed inability to establish a persistent infection was associated with development of CD8 cytotoxic T cells (CTL) that kill intracellular bacteria. Further comparative studies ex vivo with Mbv Calmette-Guérin (BCG) and a BCG rel deletion mutant revealed no clear difference in development of CTL in vitro. As reported, a study of the recall response was conducted with cattle vaccinated with either BCG or with BCGrel, to determine if information could be obtained that would show how gene products under control of rel interfere with the CTL response to mycobacterial pathogens in vivo. The study revealed the CTL response elicited by vaccination with BCG was impaired, in comparison with the response elicited by BCGrel. Comparative analysis of the recall response ex vivo revealed the functional impairment was not associated with the timing of appearance of the recall response, expression of IFN-γ, TNF-α, IL-17, or IL-22, or molecules that mediate intracellular killing. Further studies are needed to determine how CD8 CTL functional activity is modulated in vivo by gene products regulated by rel.