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Cell Microbiol. 2018 Sep 21:e12956. doi: 10.1111/cmi.12956. [Epub ahead of print]

Streptolysin-induced endoplasmic reticulum stress promotes group A Streptococcal host-associated biofilm formation and necrotising fasciitis.

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Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
School of Biological Sciences, Nanyang Technological University, Singapore.
Cellular and Molecular Mechanisms of Inflammation, Campus for Research Excellence and Technological Enterprise (CREATE), Department of Microbiology and Immunology, National University of Singapore (NUS)-The Hebrew University of Jerusalem (HUJ), Singapore.
Singapore Centre for Environmental Life Sciences Engineering, Interdisciplinary Graduate School, Nanyang Technological University, Singapore.
Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Institute for Medical Research, Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, Israel.


Group A Streptococcus (GAS) is a human pathogen that causes infections ranging from mild to fulminant and life-threatening. Biofilms have been implicated in acute GAS soft-tissue infections such as necrotising fasciitis (NF). However, most in vitro models used to study GAS biofilms have been designed to mimic chronic infections and insufficiently recapitulate in vivo conditions along with the host-pathogen interactions that might influence biofilm formation. Here, we establish and characterise an in vitro model of GAS biofilm development on mammalian cells that simulates microcolony formation observed in a mouse model of human NF. We show that on mammalian cells, GAS forms dense aggregates that display hallmark biofilm characteristics including a 3D architecture and enhanced tolerance to antibiotics. In contrast to abiotic-grown biofilms, host-associated biofilms require the expression of secreted GAS streptolysins O and S (SLO, SLS) that induce endoplasmic reticulum (ER) stress in the host. In an in vivo mouse model, the streptolysin null mutant is attenuated in both microcolony formation and bacterial spread, but pretreatment of soft-tissue with an ER stressor restores the ability of the mutant to form wild-type-like microcolonies that disseminate throughout the soft tissue. Taken together, we have identified a new role of streptolysin-driven ER stress in GAS biofilm formation and NF disease progression.


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