title: Flesh-eating Streptococcus pyogenes triggers the expression of receptor activator of nuclear factor-κB ligand.
abstract: Human CD46 is a receptor for the M protein of group A streptococcus (GAS). The emm1 GAS strain GAS472 was isolated from a patient suffering from streptococcal toxic shock-like syndrome. Human CD46-expressing transgenic (Tg) mice developed necrotizing fasciitis associated with osteoclast-mediated progressive and severe bone destruction in the hind paws 3 days after subcutaneous infection with 5 × 10(5) colony-forming units of GAS472. GAS472 infection induced expression of the receptor activator of nuclear factor-κB ligand (RANKL) while concomitantly reducing osteoprotegerin expression in the hind limb bones of CD46 Tg mice. Micro-computed tomography analysis of the bones suggested that GAS472 infection induced local bone erosion and systemic bone loss in CD46 Tg mice. Because treatment with monoclonal antibodies (mAbs) against mouse CD4(+) and CD8(+) T lymphocytes did not inhibit osteoclastogenesis, T lymphocyte-derived RANKL was not considered a major contributor to massive bone loss during GAS472 infection. However, immunohistochemical analysis of the hind limb bones showed that GAS472 infection stimulated RANKL production in various bone marrow cells, including fibroblast-like cells. Treatment with a mAb against mouse RANKL significantly inhibited osteoclast formation and bone resorption. These data suggest that increased expression of RANKL in heterogeneous bone marrow cells provoked bone destruction during GAS infection.
authors.affiliation: Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan. hmastui@lisci.kitasato-u.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan.|National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Haruno
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Biomedical Laboratory, Biochemical Research Center, Kitasato Institute Hospital, Kitasato University, Minato-ku, Tokyo, 108-8642, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Takizawa
authors.affiliation: Biomedical Laboratory, Biochemical Research Center, Kitasato Institute Hospital, Kitasato University, Minato-ku, Tokyo, 108-8642, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: Research and Education Center for Clinical Pharmacy, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Anders
authors.initials: A
authors.lastname: Øverby
authors.affiliation: Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan.|Laboratory of Molecular Cell Biology, Nihon University School of Pharmacy, 7-7-1 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan.
authors.forename: Somay Y
authors.initials: SY
authors.lastname: Murayama
authors.affiliation: Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000276:immunology / Q000382:microbiology; D015870:Gene Expression; D006614:Hindlimb / Q000382:microbiology / Q000473:pathology; D006801:Humans; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010011:Osteocytes / Q000378:metabolism; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D013290:Streptococcal Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D013297:Streptococcus pyogenes / Q000276:immunology*; D013977:Tibia / Q000382:microbiology / Q000473:pathology; D015533:Transcriptional Activation / Q000276:immunology*
chemical_list: C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse