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Background  The  Mycobacterium tuberculosis  genome encodes two peptide transporters encoded by Rv3665c-Rv3662c and Rv1280c-Rv1283c. Both belong to the family of ABC transporters containing two nucleotide-binding subunits, two integral membrane proteins and one substrate-binding polypeptide. However, little is known about their functions in  M. tuberculosis . Here we report functional characterization of the Rv1280c-Rv1283c-encoded transporter and its substrate-binding polypeptide OppA MTB .    Methodology/Principal Findings  OppA MTB  was capable of binding the tripeptide glutathione and the nonapeptide bradykinin, indicative of a somewhat broad substrate specificity. Amino acid residues G109, N110, N230, D494 and F496, situated at the interface between domains I and III of OppA, were required for optimal peptide binding. Complementaton of an  oppA  knockout mutant of  M. smegmatis  with OppA MTB  confirmed the role of this transporter in importing glutathione and the importance of the aforesaid amino acid residues in peptide transport. Interestingly, this transporter regulated the ability of  M .  tuberculosis  to lower glutathione levels in infected compared to uninfected macrophages. This ability was partly offset by inactivation of  oppD . Concomitantly, inactivation of  oppD  was associated with lowered levels of methyl glyoxal in infected macrophages and reduced apoptosis-inducing ability of the mutant. The ability to induce the production of the cytokines IL-1β, IL-6 and TNF-α was also compromised after inactivation of  oppD .    Conclusions  Taken together, these studies uncover the novel observations that this peptide transporter modulates the innate immune response of macrophages infected with  M. tuberculosis .

An Oligopeptide Transporter of Mycobacterium tuberculosis Regulates Cytokine Release and Apoptosis of Infected Macrophages