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Infection and Immunity, September 2008, p. 4269-4281, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.01735-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Mycobacterium tuberculosis Rpf Double-Knockout Strain Exhibits Profound Defects in Reactivation from Chronic Tuberculosis and Innate Immunity Phenotypes{triangledown}

Eleanor Russell-Goldman,2 Jiayong Xu,1 Xiaobing Wang,1 John Chan,1,2 and JoAnn M. Tufariello1*

Departments of Medicine,1 Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 104612

Received 26 December 2007/ Returned for modification 14 February 2008/ Accepted 16 June 2008

Resuscitation-promoting factors (Rpfs), apparent peptidoglycan hydrolases, have been implicated in the reactivation of dormant bacteria. We previously demonstrated that deletion of rpfB impaired reactivation of Mycobacterium tuberculosis in a mouse model. Because M. tuberculosis encodes five Rpf paralogues, redundant functions among the family members might obscure rpf single-knockout phenotypes. A series of rpf double knockouts were therefore generated. One double mutant, {Delta}rpfAB, exhibited several striking phenotypes. Consistent with the proposed cell wall-modifying function of Rpfs, {Delta}rpfAB exhibited an altered colony morphology. Although {Delta}rpfAB grew comparably to the parental strain in axenic culture, in vivo it exhibited deficiency in reactivation induced in C57BL/6 mice by the administration of nitric oxide synthase inhibitor (aminoguanidine) or by CD4+ T-cell depletion. Notably, the reactivation deficiency of {Delta}rpfAB was more severe than that of {Delta}rpfB in aminoguanidine-treated mice. A similar deficiency was observed in {Delta}rpfAB reactivation from a drug-induced apparently sterile state in infected NOS2–/– mice upon cessation of antimycobacterial therapy. Secondly, {Delta}rpfAB showed a persistence defect not seen with the {Delta}rpfB or {Delta}rpfA single mutants. Interestingly, {Delta}rpfAB exhibited impaired growth in primary mouse macrophages and induced higher levels of the proinflammatory cytokines tumor necrosis factor alpha and interleukin 6. Simultaneous reintroduction of rpfA and rpfB into the double-knockout strain complemented the colony morphology and macrophage cytokine secretion phenotypes. Phenotypes related to cell wall composition and macrophage responses suggest that M. tuberculosis Rpfs may influence the outcome of reactivation, in part, by modulating innate immune responses to the bacterium.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Forchheimer Building, Room 406, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2679. Fax: (718) 430-8725. E-mail: tufariel{at}aecom.yu.edu

{triangledown} Published ahead of print on 30 June 2008.

Editor: F. C. Fang

Infection and Immunity, September 2008, p. 4269-4281, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.01735-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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