
Deletion of theMycobacterium tuberculosisResuscitation-Promoting Factor Rv1009 Gene Results in Delayed Reactivation from Chronic Tuberculosis
Author(s) -
Jo Ann M. Tufariello,
Kaixia Mi,
Jiayong Xu,
Yukari C. Manabe,
Anup Kumar Kesavan,
Joshua E. Drumm,
Kathryn E. Tanaka,
William R. Jacobs,
John Chan
Publication year - 2006
Publication title -
infection and immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.508
H-Index - 220
eISSN - 1070-6313
pISSN - 0019-9567
DOI - 10.1128/iai.74.5.2985-2995.2006
Subject(s) - mycobacterium tuberculosis , biology , tuberculosis , immunology , population , in vivo , mutant , gene , pathology , medicine , genetics , environmental health
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. tuberculosis in 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. tuberculosis proteins, called resuscitation promoting factors (Rpfs), in regulating mycobacterial growth. We studied the in vivo role ofM. tuberculosis rpf genes in an established mouse model ofM. tuberculosis persistence and reactivation. After an aerosol infection with theM. tuberculosis Erdman wild type (Erdman) or single-deletionrpf mutants to establish chronic infections in mice, reactivation was induced by administration of the nitric oxide (NO) synthase inhibitor aminoguanidine. Of the fiverpf deletion 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 ofrpf gene 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 thatrpf gene expression may be regulated in a growth phase-dependent manner. To our knowledge, ΔRv1009 is the firstM. tuberculosis mutant to have a specific defect in reactivation without accompanying growth defects in vitro or during acute infection in vivo.