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Group A Streptococcus tissue invasion by CD44-mediated cell signalling

Nature volume 414, pages 648–652 (2001)Cite this article

Abstract

Streptococcus pyogenes (also known as group A Streptococcus, GAS), the agent of streptococcal sore throat and invasive soft-tissue infections, attaches to human pharyngeal or skin epithelial cells through specific recognition of its hyaluronic acid capsular polysaccharide by the hyaluronic-acid-binding protein CD44 (refs 1, 2). Because ligation of CD44 by hyaluronic acid can induce epithelial cell movement on extracellular matrix3,4,5, we investigated whether molecular mimicry by the GAS hyaluronic acid capsule might induce similar cellular responses. Here we show that CD44-dependent GAS binding to polarized monolayers of human keratinocytes induced marked cytoskeletal rearrangements manifested by membrane ruffling and disruption of intercellular junctions. Transduction of the signal induced by GAS binding to CD44 on the keratinocyte surface involved Rac1 and the cytoskeleton linker protein ezrin, as well as tyrosine phosphorylation of cellular proteins. Studies of bacterial translocation in two models of human skin indicated that cell signalling triggered by interaction of the GAS capsule with CD44 opened intercellular junctions and promoted tissue penetration by GAS through a paracellular route. These results support a model of host cytoskeleton manipulation and tissue invasion by an extracellular bacterial pathogen.

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Figure 1: Induction of lamellipodia formation by GAS binding to keratinocytes.
Figure 2: Confocal microscopy images of GAS interaction with keratinocytes expressing dominant negative (N17) or constitutively active (L61) Rac1.
Figure 3: GAS-induced disruption of intercellular junctions.
Figure 4: GAS translocation across model epithelia.

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Acknowledgements

We thank E. Meluleni for preparation of the histology specimens; M. Lowe for assistance with the confocal microscopy; and R. Stearns for assistance with scanning electron microscopy. This work was supported by the National Institutes of Health.

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Authors and Affiliations

  1. Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Colette Cywes & Michael R. Wessels

  2. Division of Infectious Diseases, Children's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Michael R. Wessels

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  1. Colette Cywes
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  2. Michael R. Wessels
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Correspondence to Michael R. Wessels.

Supplementary information

Figure 1 a,b

(JPG 36.24 KB)

Figure 1 c

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Confocal microscopy images demonstrating localization of keratinocyte-cell signaling molecules to the site of attachment of wild-type, but not acapsular, GAS. a, Samples were labeled with antibody to Rac1 (green) and to GAS (red). The left panels show merged images from the green and red channels. In the right panels, co-localization of green and red is shown in yellow: the images demonstrate co-localization of Rac1 at the site of attachment of wild-type GAS strain 950771 (cap+, arrows), but not acapsular mutant strain 188 (cap-). b, Samples were labeled with antibody to ezrin (green) and to GAS (red). The left panel shows merged images from the green and red channels. In the right panels, co-localization of green and red is shown in yellow: the images demonstrate co-localization of ezrin at the site of attachment of wild-type (cap+, arrows), but not acapsular (cap-), GAS. c, Samples were labeled with antibody to GAS (blue), to CD44 (red), and to phosphotyrosine (green), all of which are visible in the merged images in the left panels. In the other panels, co-localization of each of the potential fluorophore pairs is assessed: CD44 with phosphotyrosine appears yellow, GAS with CD44 appears pink, and GAS with phosphotyrosine appears blue. Co-localization of CD44 and phosphotyrosine is observed at the site of attachment to the keratinocyte of wild-type (cap+), but not acapsular (cap-), GAS.

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Cywes, C., Wessels, M. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414, 648–652 (2001). https://doi.org/10.1038/414648a

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