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Flesh-eating Streptococcus pyogenes triggers the expression of receptor activator of nuclear factor-κB ligand

Hidenori Matsui1, Yuriko Nakatani2,3, Haruno Yoshida2

  • 1Department of Infection Control and Immunology, Kitasato Institute for Life Sciences, Kitasato University, Minato-ku, Tokyo, 108-8641, Japan. hmastui@lisci.kitasato-u.ac.jp.

Cellular Microbiology
|February 20, 2016
PubMed

Insights

Group A Streptococcus (GAS) infection in CD46 transgenic mice caused severe bone destruction. This bone loss was driven by increased receptor activator of nuclear factor-κB ligand (RANKL) produced by bone marrow cells, not T-cells.

Area of Science:

  • Immunology
  • Microbiology
  • Orthopedics

Background:

  • Human CD46 acts as a receptor for the M protein of Group A Streptococcus (GAS).
  • A specific GAS emm1 strain, GAS472, was isolated from a patient with streptococcal toxic shock-like syndrome.

Purpose of the Study:

  • To investigate the mechanism of bone destruction caused by GAS infection in a human CD46-expressing transgenic mouse model.
  • To determine the role of receptor activator of nuclear factor-κB ligand (RANKL) in GAS-induced bone loss.

Main Methods:

  • Subcutaneous infection of CD46 transgenic mice with GAS472.
  • Micro-computed tomography (Micro-CT) for bone analysis.
  • Immunohistochemistry to assess RANKL and osteoprotegerin expression.
  • Treatment with monoclonal antibodies against T-lymphocytes and RANKL.

Main Results:

  • GAS472 infection led to necrotizing fasciitis and severe, progressive bone destruction in the hind paws of CD46 Tg mice.
  • GAS infection increased RANKL expression and decreased osteoprotegerin in the hind limb bones.
  • Micro-CT revealed local bone erosion and systemic bone loss.
  • RANKL production was stimulated in various bone marrow cells, including fibroblast-like cells, and blocking RANKL inhibited osteoclast formation and bone resorption.

Conclusions:

  • GAS infection can induce significant bone destruction mediated by osteoclast activation.
  • Increased RANKL expression in heterogeneous bone marrow cells is a key factor in GAS-induced bone loss.
  • Targeting RANKL may be a therapeutic strategy for managing bone destruction during GAS infections.

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