title: The SecA2 secretion factor of Mycobacterium tuberculosis promotes growth in macrophages and inhibits the host immune response.
abstract: 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 DeltasecA2 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 DeltasecA2 mutant was defective for growth in macrophages from C57BL/6 mice. The DeltasecA2 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 DeltasecA2 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.
authors.affiliation: Department of Microbiology and Immunology, C.B. 7290, University of North Carolina, Rm. 804 Mary Ellen Jones Building, Chapel Hill, NC 27599-7290, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Kurtz
authors.forename: Karen P
authors.initials: KP
authors.lastname: McKinnon
authors.forename: Marschall S
authors.initials: MS
authors.lastname: Runge
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
authors.forename: Miriam
authors.initials: M
authors.lastname: Braunstein
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000502:physiology*; D000336:Aerosols; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D007108:Immune Tolerance; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010641:Phenotype; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology
chemical_list: D000336:Aerosols; D001426:Bacterial Proteins; D016207:Cytokines; D026901:Membrane Transport Proteins; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000251:Adenosine Triphosphatases; C442123:SecA2 protein, Mycobacterium