Abstract
To cause disease and persist in a host, pathogenic and commensal microbes must adhere to tissues. Colonization and infection depend on specific molecular interactions at the host-microbe interface that involve microbial surface proteins, or adhesins. To date, adhesins are only known to bind to host receptors non-covalently. Here we show that the streptococcal surface protein SfbI mediates covalent interaction with the host protein fibrinogen using an unusual internal thioester bond as a 'chemical harpoon'. This cross-linking reaction allows bacterial attachment to fibrin and SfbI binding to human cells in a model of inflammation. Thioester-containing domains are unexpectedly prevalent in Gram-positive bacteria, including many clinically relevant pathogens. Our findings support bacterial-encoded covalent binding as a new molecular principle in host-microbe interactions. This represents an as yet unexploited target to treat bacterial infection and may also offer novel opportunities for engineering beneficial interactions.
Highlights
For commensal and pathogenic bacteria, adhesion to host surfaces is a pre-requisite for colonization and infection, and is mediated by surface-presented adhesins (Pizarro-Cerdaand Cossart, 2006)
Bacterial adhesins bind either directly to integral host cell surface components, such as integrins or carbohydrates, or they interact with components of the extracellular matrix resulting in indirect binding to receptors on the host cell surface (Kline et al, 2009)
Walden, Edwards et al made a mutant version of SfbI that did not contain a thioester, and found that it could not interact with fibrinogen nor bind to human cells
Summary
For commensal and pathogenic bacteria, adhesion to host surfaces is a pre-requisite for colonization and infection, and is mediated by surface-presented adhesins (Pizarro-Cerdaand Cossart, 2006). Walden, Edwards et al made a mutant version of SfbI that did not contain a thioester, and found that it could not interact with fibrinogen nor bind to human cells. The structure of CpTIE-TED: Cys138Ala is essentially identical to the native protein (Figure 2—figure supplement 1B,C), confirming that internal thioesters are not structural determinants (Walden et al, 2014).
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