6QX4

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

(2019) Nat Microbiol 4: 1805-1814

• PubMed: 31308522 Search on PubMed
• DOI: https://doi.org/10.1038/s41564-019-0499-1
• Primary Citation of Related Structures:  
  6HHU, 6QX4


• PubMed 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 ^1,2 . 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 (Sap ^AD ) and show that the disintegration of the S-layer attenuates the growth of B. anthracis and the pathology of anthrax in vivo. Sap ^AD 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.

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Organizational Affiliation: 

Structural and Molecular Microbiology, Structural Biology Research Center, VIB, Brussels, Belgium. antonella.fioravanti@vub.be.