Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity

David Gerlach, Yinglan Guo, Cristina De Castro, Sun-Hwa Kim, Katja Schlatterer, Fei-Fei Xu, Claney Pereira, Peter H. Seeberger, Sara Ali, Jeroen Codée, Wanchat Sirisarn, Berit Schulte, Christiane Wolz, Jesper Larsen, Antonio Molinaro, Bok Luel Lee, Guoqing Xia, Thilo Stehle () and Andreas Peschel ()
Additional contact information
David Gerlach: University of Tübingen
Yinglan Guo: University of Tübingen
Cristina De Castro: University of Naples
Sun-Hwa Kim: Pusan National University
Katja Schlatterer: University of Tübingen
Fei-Fei Xu: Max-Planck-Institute for Colloids and Interfaces
Claney Pereira: Max-Planck-Institute for Colloids and Interfaces
Peter H. Seeberger: Max-Planck-Institute for Colloids and Interfaces
Sara Ali: Leiden University
Jeroen Codée: Leiden University
Wanchat Sirisarn: University of Manchester, Manchester Academic Health Science Centre
Berit Schulte: Partner Site Tübingen
Christiane Wolz: Partner Site Tübingen
Jesper Larsen: Statens Serum Institut
Antonio Molinaro: University of Naples
Bok Luel Lee: Pusan National University
Guoqing Xia: University of Manchester, Manchester Academic Health Science Centre
Thilo Stehle: University of Tübingen
Andreas Peschel: University of Tübingen

Nature, 2018, vol. 563, issue 7733, 705-709

Abstract: Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans1,2. Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients3. Previous vaccine development programs have not been successful4. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA), a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc)5,6. It is currently unknown whether the immune evasion capacities of MRSA are due to variation of dominant surface epitopes such as those associated with WTA. Here we show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones CC5 and CC398, respectively, contain prophages that encode an alternative WTA glycosyltransferase. This enzyme, TarP, transfers GlcNAc to a different hydroxyl group of the WTA RboP than the standard enzyme TarS7, with important consequences for immune recognition. TarP-glycosylated WTA elicits 7.5–40-fold lower levels of immunoglobulin G in mice than TarS-modified WTA. Consistent with this, human sera contained only low levels of antibodies against TarP-modified WTA. Notably, mice immunized with TarS-modified WTA were not protected against infection with tarP-expressing MRSA, indicating that TarP is crucial for the capacity of S. aureus to evade host defences. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDP-GlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP. Our study reveals an immune evasion strategy of S. aureus based on averting the immunogenicity of its dominant glycoantigen WTA. These results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defences.

Keywords: Methicillin-resistant Staphylococcus Aureus (MRSA); MRSA Clones; Immunocompromized Patients; Wall Teichoic Acid (WTA); Siphophages (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (2)

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DOI: 10.1038/s41586-018-0730-x

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