The role of resuscitation promoting factors in pathogenesis and reactivation of Mycobacterium tuberculosis during intra-peritoneal infection in mice

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Abstract
Background: Mycobacterium tuberculosiscan enter into a dormant state which has resulted in one third of the world's population being infected with latent tuberculosis making the study of latency and reactivation of utmost importance.M. tuberculosisencodes five resuscitation promoting factors (Rpfs) that bear strong similarity to a lysozyme-like enzyme previously implicated in reactivation of dormant bacteriain vitro.We have developed an intraperitoneal infection model in mice, with immune modulation, that models chronic infection with similar properties in mouse lungs as those observed in the murine aerosol infection model. We have assessed the behavior of mutants that lack two or threerpfgenes in different combinations in our intraperitoneal model.Methods: C57Bl/6 mice were intraperitonealy infected with H37Rv wild typeM. tuberculosisor mutant strains that lacked two or threerpfgenes in different combinations. After 90 days of infection aminoguanidine (AG) or anti-TNFα antibodies were administrated. Organ bacillary loads were determined at various intervals post infection by plating serial dilutions of organ homogenates and enumerating bacteria.Results: We found that therpftriple and double mutants tested were attenuated in their ability to disseminate to mouse lungs after intraperitoneal administration and were defective in their ability to re-grow after immunosuppression induced by administration of aminoguanidine and anti-TNFα antibodies.Conclusion: Rpf proteins may have a significant physiological role for development of chronic TB infection and its reactivationin vivo.