Potent antimycobacterial activity of mouse secretory leukocyte protease inhibitor.
Secretory leukocyte protease inhibitor (SLPI) has multiple functions, including inhibition of protease activity, microbial growth, and inflammatory responses. In this study, we demonstrate that mouse SLPI is critically involved in innate host defense against pulmonary mycobacterial infection. During the early phase of respiratory infection with Mycobacterium bovis bacillus Calmette-Guérin, SLPI was produced by bronchial and alveolar epithelial cells, as well as alveolar macrophages, and secreted into the alveolar space. Recombinant mouse SLPI effectively inhibited in vitro growth of bacillus Calmette-Guérin and Mycobacterium tuberculosis through disruption of the mycobacterial cell wall structure. Each of the two whey acidic protein domains in SLPI was sufficient for inhibiting mycobacterial growth. Cationic residues within the whey acidic protein domains of SLPI were essential for disruption of mycobacterial cell walls. Mice lacking SLPI were highly susceptible to pulmonary infection with M. tuberculosis. Thus, mouse SLPI is an essential component of innate host defense against mycobacteria at the respiratory mucosal surface.
Nishimura
Junichi
J
Deparment of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Saiga
Hiroyuki
H
Sato
Shintaro
S
Okuyama
Megumi
M
Kayama
Hisako
H
Kuwata
Hirotaka
H
Matsumoto
Sohkichi
S
Nishida
Toshirou
T
Sawa
Yoshiki
Y
Akira
Shizuo
S
Yoshikai
Yasunobu
Y
Yamamoto
Masahiro
M
Takeda
Kiyoshi
K
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D002473:Cell Wall / Q000276:immunology / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology*; D017434:Protein Structure, Tertiary; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000201:enzymology / Q000276:immunology / Q000382:microbiology
D000995:Antitubercular Agents; D006131:Growth Inhibitors; D053481:Secretory Leukocyte Peptidase Inhibitor