Deletion of theMycobacterium tuberculosisResuscitation-Promoting Factor Rv1009 Gene Results in Delayed Reactivation from Chronic Tuberculosis

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Abstract
Approximately one-third of the human population is latently infected withMycobacterium tuberculosis, comprising a critical reservoir for disease reactivation. Despite the importance of latency in maintainingM. tuberculosisin the human population, little is known about the mycobacterial factors that regulate persistence and reactivation. Previous in vitro studies have implicated a family of five relatedM. tuberculosisproteins, called resuscitation promoting factors (Rpfs), in regulating mycobacterial growth. We studied the in vivo role ofM. tuberculosis rpfgenes in an established mouse model ofM. tuberculosispersistence and reactivation. After an aerosol infection with theM. tuberculosisErdman wild type (Erdman) or single-deletionrpfmutants to establish chronic infections in mice, reactivation was induced by administration of the nitric oxide (NO) synthase inhibitor aminoguanidine. Of the fiverpfdeletion mutants tested, one (ΔRv1009) exhibited a delayed reactivation phenotype, manifested by delayed postreactivation growth kinetics and prolonged median survival times among infected animals. Immunophenotypic analysis suggested differences in pulmonary B-cell responses between Erdman- and ΔRv1009-infected mice at advanced stages of reactivation. Analysis ofrpfgene expression in the lungs of Erdman-infected mice revealed that relative expression of four of the fiverpf-like genes was diminished at late times following reactivation, when bacterial numbers had increased substantially, suggesting thatrpfgene expression may be regulated in a growth phase-dependent manner. To our knowledge, ΔRv1009 is the firstM. tuberculosismutant to have a specific defect in reactivation without accompanying growth defects in vitro or during acute infection in vivo.