Adaptation of the group A Streptococcus adhesin Scl1 to bind fibronectin type III repeats within wound-associated extracellular matrix: implications for cancer therapy.

Dudley H Mcnitt,Livingston Van De Water,Jessica L Allen,Scott A Weed,River A Hames,Rita Berisio,Slawomir Lukomski,Soo Jeon Choi

doi:10.1111/mmi.14317

Abstract

SummaryThe human‐adapted pathogen group A Streptococcus (GAS) utilizes wounds as portals of entry into host tissue, wherein surface adhesins interact with the extracellular matrix, enabling bacterial colonization. The streptococcal collagen‐like protein 1 (Scl1) is a major adhesin of GAS that selectively binds to two fibronectin type III (FnIII) repeats within cellular fibronectin, specifically the alternatively spliced extra domains A and B, and the FnIII repeats within tenascin‐C. Binding to FnIII repeats was mediated through conserved structural determinants present within the Scl1 globular domain and facilitated GAS adherence and biofilm formation. Isoforms of cellular fibronectin that contain extra domains A and B, as well as tenascin‐C, are present for several days in the wound extracellular matrix. Scl1‐FnIII binding is therefore an example of GAS adaptation to the host's wound environment. Similarly, cellular fibronectin isoforms and tenascin‐C are present in the tumor microenvironment. Consistent with this, FnIII repeats mediate GAS attachment to and enhancement of biofilm formation on matrices deposited by cancer‐associated fibroblasts and osteosarcoma cells. These data collectively support the premise for utilization of the Scl1‐FnIII interaction as a novel method of anti‐neoplastic targeting in the tumor microenvironment.

Highlights

Group A Streptococcus (GAS or Streptococcus pyogenes) is an obligate human pathogen that is responsible for over 700 million infections worldwide each year (Carapetis et al, 2005)
We previously reported that streptococcal collagen-like protein 1 (Scl1) binds to the wound-associated fibronectin type III repeat, EDA, facilitating GAS colonization and biofilm formation on EDA/cellular fibronectin (cFn) coating and on matrices deposited by normal human dermal fibroblasts (Oliver-Kozup et al, 2013)
We have shown that Scl1 binds to cFn, but not plasma fibronectin (Caswell et al, 2010), through direct binding to EDA (Oliver-Kozup et al, 2013)

Summary

Introduction

Group A Streptococcus (GAS or Streptococcus pyogenes) is an obligate human pathogen that is responsible for over 700 million infections worldwide each year (Carapetis et al, 2005). Infection by GAS can result in diseases that range in severity, from highly prevalent superficial infections to fatal conditions (Carapetis et al, 2005). GAS infection can lead to the development of post-infectious autoimmune sequelae (Bisno et al, 1970; Swedo et al., 1997; Cunningham, 2000). Invasive infections and autoimmune sequelae result in over 500,000 deaths globally each year (Carapetis et al, 2005; Ralph and Carapetis, 2013), placing GAS among the top 10 most lethal bacteria (Ralph and Carapetis, 2013). Superficial GAS infections account for the majority (~95.5%) of infections, mostly affecting children; GAS asymptomatically colonizes the throat and skin of 5–25% of children of the general population (Efstratiou and Lamagni, 2016). GAS isolates are subtyped based on sequence polymorphisms within the 5′-hypervariable end of the emm gene, encoding the

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Discussion

Conclusion