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Infection and Immunity, December 2006, p. 6855-6864, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01022-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The SecA2 Secretion Factor of Mycobacterium tuberculosis Promotes Growth in Macrophages and Inhibits the Host Immune Response{triangledown}

Sherry Kurtz,1 Karen P. McKinnon,1 Marschall S. Runge,2 Jenny P.-Y. Ting,1 and Miriam Braunstein1*

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599-7290,1 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina2

Received 29 June 2006/ Returned for modification 3 August 2006/ Accepted 28 September 2006

The SecA protein is present in all bacteria, and it is a central component of the general Sec-dependent protein export pathway. An unusual property of Mycobacterium tuberculosis is the presence of two SecA proteins: SecA1, the essential "housekeeping" SecA, and SecA2, the accessory secretion factor. Here, we report that a {Delta}secA2 mutant of M. tuberculosis was defective for growth in the early stages of low-dose aerosol infection of C57BL/6 mice, a time during which the bacillus is primarily replicating in macrophages. Consistent with this in vivo phenotype, we found that the {Delta}secA2 mutant was defective for growth in macrophages from C57BL/6 mice. The {Delta}secA2 mutant was also attenuated for growth in macrophages from phox–/– mice and from NOS2–/– mice. These mice are defective in the reactive oxygen intermediate (ROI)-generating phagocyte oxidase and the reactive nitrogen intermediate (RNI)-generating inducible nitric oxide synthase, respectively. This indicated a role for SecA2 in the intracellular growth of M. tuberculosis that is independent of protecting against these ROIs or RNIs. Macrophages infected with the {Delta}secA2 mutant produced higher levels of tumor necrosis factor alpha, interleukin-6, RNI, and gamma interferon-induced major histocompatibility complex class II. This demonstrated a function for M. tuberculosis SecA2 in suppressing macrophage immune responses, which could explain the role of SecA2 in intracellular growth. Our results provide another example of a relationship between M. tuberculosis virulence and inhibition of the host immune response.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, C.B. 7290, Mary Ellen Jones Bldg., Rm. 804, University of North Carolina, Chapel Hill, NC 27599-7290. Phone: (919) 966-5051. Fax: (919) 962-8103. E-mail: miriam_braunstein{at}med.unc.edu.

{triangledown} Published ahead of print on 9 October 2006.

Editor: J. L. Flynn

Infection and Immunity, December 2006, p. 6855-6864, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.01022-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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