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Structure of S-layer protein Sap reveals a mechanism for therapeutic intervention in anthrax

DOI: 10.1038/s41564-019-0499-1 DOI Help

Authors: Antonella Fioravanti (VIB; Vrije Universiteit Brussel) , Filip Van Hauwermeiren (Vlaams Instituut voor Biotechnologie; Ghent University; Pharmaceutical Companies of Johnson & Johnson) , Sander E. Van Der Verren (VIB; Vrije Universiteit Brussel) , Wim Jonckheere (VIB; Vrije Universiteit Brussel) , Amanda Goncalves (UGent-VIB) , Els Pardon (VIB; Vrije Universiteit Brussel) , Jan Steyaert (VIB; Vrije Universiteit Brussel) , Henri De Greve (VIB; Vrije Universiteit Brussel) , Mohamed Lamkanfi (VIB; Vrije Universiteit Brussel) , Han Remaut (VIB; Vrije Universiteit Brussel)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Microbiology , VOL 8

State: Published (Approved)
Published: July 2019
Diamond Proposal Number(s): 12718 , 17150

Abstract: Anthrax is an ancient and deadly disease caused by the spore-forming bacterial pathogen Bacillus anthracis. At present, anthrax mostly affects wildlife and livestock, although it remains a concern for human public health—primarily for people who handle contaminated animal products and as a bioterrorism threat due to the high resilience of spores, a high fatality rate of cases and the lack of a civilian vaccination programme. The cell surface of B. anthracis is covered by a protective paracrystalline monolayer—known as surface layer or S-layer—that is composed of the S-layer proteins Sap or EA1. Here, we generate nanobodies to inhibit the self-assembly of Sap, determine the structure of the Sap S-layer assembly domain (SapAD) and show that the disintegration of the S-layer attenuates the growth of B. anthracis and the pathology of anthrax in vivo. SapAD comprises six β-sandwich domains that fold and support the formation of S-layers independently of calcium. Sap-inhibitory nanobodies prevented the assembly of Sap and depolymerized existing Sap S-layers in vitro. In vivo, nanobody-mediated disruption of the Sap S-layer resulted in severe morphological defects and attenuated bacterial growth. Subcutaneous delivery of Sap inhibitory nanobodies cleared B. anthracis infection and prevented lethality in a mouse model of anthrax disease. These findings highlight disruption of S-layer integrity as a mechanism that has therapeutic potential in S-layer-carrying pathogens.

Journal Keywords: Bacterial infection; Bacterial structural biology; Pathogens; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography