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

Antonella Fioravanti, Filip Van Hauwermeiren, Sander E Van der Verren, Wim Jonckheere, Amanda Goncalves, Els Pardon, Jan Steyaert, Henri De Greve, Mohamed Lamkanfi, Han Remaut

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 programme1,2. 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.

Original languageEnglish
Pages (from-to)1805–1814
Number of pages10
JournalNature Microbiology
Volume4
Issue number11
Early online date15 Jul 2019
DOIs
Publication statusPublished - Nov 2019

Keywords

  • anthrax
  • antibacterial
  • bacterial cell surface
  • S-layer
  • nanobody therapy

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