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J. Biol. Chem., Vol. 282, Issue 8, 5133-5142, February 23, 2007

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The Mycobacterium tuberculosis Cell-surface Glycoprotein Apa as a Potential Adhesin to Colonize Target Cells via the Innate Immune System Pulmonary C-type Lectin Surfactant Protein A^*

From the Institut de Pharmacologie et de Biologie Structurale, CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France

Tuberculosis is still a major health problem, and understanding the mechanism by which Mycobacterium tuberculosis (Mtb) invades and colonizes its host target cells remains an important issue for the control of infection. The innate immune system C-type lectins (C-TLs), including the human pulmonary surfactant protein A (PSP-A), have been recently identified as determinant players in the early recognition of the invading pathogen and in mounting the host defense response. Although the antigenic lipoglycan mannosylated lipoarabinomannan is currently considered to be the major C-TL target on the mycobacterial surface, the recognition by some C-TLs of the only mycobacterial species composing the "Mtb complex" indicates that mannosylated lipoarabinomannan cannot account alone for this specificity. Thus, we searched for the mycobacterial molecules targeted by human PSP-A, focusing our attention on the Mtb surface glycoproteins. We developed an original functional proteomic approach based on a lectin blot assay using crude human bronchoalveolar lavage fluid as a source of physiological PSP-A. Combined with selective cell-surface protein extraction and mass spectrometry peptide mapping, this strategy allowed us to identify the Apa (alanine- and proline-rich antigenic) glycoprotein as new potential target for PSP-A. This result was supported by direct binding of PSP-A to purified Apa. Moreover, EDTA addition or deglycosylation of purified Apa samples completely abolished the interaction, demonstrating that the interaction is calcium- and mannose-dependent, as expected. Finally, we provide convincing evidence that Apa, formerly considered as mainly secreted, is associated with the cell wall for a sufficiently long time to aid in the attachment of PSP-A. Because, to date, Apa seems to be restricted to the Mtb complex strains, we propose that it may account for the selective recognition of those strains by PSP-A and other immune system C-TLs containing homologous functional domains.

Received for publication, October 31, 2006 , and in revised form, December 7, 2006.

^* This work was supported in part by Grants ACC SV6 9506005 and ACC SV14 1411587 from the Mission Scientifique et Technique du Ministère de l'Education Nationale, de l'Enseignement Supérieur, et de la Recherche and by Grant RECH/9702343 from the Région Midi-Pyrénées. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures."

¹ Ministère de l'Education Nationale, de l'Enseignement Supérieur, et de la Recherche Fellow.

² To whom correspondence should be addressed. Tel.: 33-5-6117-5558; Fax: 33-5-6117-5994; E-mail: Michel.Riviere{at}ipbs.fr.

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