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Secretory Leukocyte Protease Inhibitor

A Secreted Pattern Recognition Receptor for Mycobacteria

¹ Department of Pharmacology, University of Buenos Aires School of Medicine, Buenos Aires, Argentina; ² Department of Biological Chemistry, University of Buenos Aires School of Sciences, Buenos Aires Argentina; ³ Servicio Derivados de Micobacterias, Instituto Nacional de Producción de Biológicos, Administración Nacional de Laboratorios e Institutos de Salud Dr. Carlos G. Malbrán, Buenos Aires, Argentina; and ⁴ División de Tisioneumonología, Hospital F. J. Muñiz, Buenos Aires, Argentina

Correspondence and requests for reprints should be addressed to H. Eduardo Chuluyan, M.D., Ph.D., 3ra Cátedra de Farmacología, Piso 9, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, CP 1121, Buenos Aires, Argentina. E-mail: echuluyan{at}fmed.uba.ar

Rationale: Human secretory leukocyte protease inhibitor (SLPI) displays bactericidal activity against pathogens such as Escherichia coli and Streptococcus. Furthermore, it has been reported that murine SLPI shows potent antimycobacterial activity.

Objectives: The aim of the present study was to investigate whether human recombinant SLPI not only kills mycobacteria but also acts as a pattern recognition receptor for the host immune system.

Methods: For the in vivo experiment, BALB/c mice were infected by intranasal instillation with Mycobacterium bovis BCG and viable BCG load in lung homogenates was later determined. For the in vitro experiments, SLPI was incubated overnight with a suspension of M. bovis BCG or the virulent strain Mycobacterium tuberculosis H37Rv, and the percentage survival as well as the binding of SLPI to mycobacteria was determined. Furthermore, bacteria phagocytosis was also determined by flow cytometry.

Measurements and Main Results: Intranasal SLPI treatment decreased the number of colony-forming units recovered from lung homogenates, indicating that SLPI interfered with M. bovis BCG infection. Moreover, SLPI decreased the viability of both M. bovis BCG and H37Rv. We demonstrated that SLPI attached to the surface of the mycobacteria by binding to pathogen-associated molecular pattern mannan-capped lipoarabinomannans and phosphatidylinositol mannoside. Furthermore, we found that in the sputum of patients with tuberculosis, mycobacteria were coated with endogenous SLPI. Finally, we showed that phagocytosis of SLPI-coated mycobacteria was faster than that of uncoated bacteria.

Conclusions: The present results demonstrate for the first time that human SLPI kills mycobacteria and is a new pattern recognition receptor for them.

Key Words: tuberculosis • secretory leukocyte protease inhibitor • phagocytosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Human secretory leukocyte protease inhibitor (SLPI) displays bactericidal activity against pathogens such as Escherichia coli and Streptococcus. Furthermore, it has been reported that murine SLPI shows potent antimycobacterial activity. What This Study Adds to the Field Human SLPI binds to Mycobacterium tuberculosis, and facilitates phagocytosis and killing of the pathogen.

 

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