noxR3, a novel gene from Mycobacterium tuberculosis, protects Salmonella typhimurium from nitrosative and oxidative stress

Reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RN I) produced by activated macrophages participate in host defense against th e facultative intracellular pathogens Mycobacterium tuberculosis and Salmon ella typhimurium. To survive within macrophages, such pathogens may have ev olved ROI and Rh? resistance mechanisms. ROI resistance pathways have been intensively studied. Much less is known about the mechanisms of resistance to RNI, To identify possible RNI resistance genes in M. tuberculosis, a myc obacterial library was expressed in S. typhimurium and subjected to selecti on by exposure to the NO donor S-nitrosoglutathione (GSNO) in concentration s sufficient to kill the vast majority of nontransformed salmonellae. Among the rare surviving recombinants was a clone expressing noxR3, a novel and previously anonymous M. tuberculosis gene predicted to encode a small, basi c protein. Expression of noxR3 protected S. typhimurium not only from GSNO and acidified nitrite but also from H2O2. noxR3 is the third gene cloned fr om M tuberculosis that has been shown to protect heterologous cells from bo th RM and ROI, This suggests diversity in the repertoire of mechanisms that help pathogens resist the oxidative and nitrosative defenses of the host.