Methicillin-resistantStaphylococcus aureus (MRSA) is a frequent cause of difficult-to-treat, often fatal infections in humans 1,2 . Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients 3 . Previous vaccine development programs have not been successful 4 . 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 TarS 7 , 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.Novel prevention and treatment strategies against major antibioticresistant pathogens such as MRSA are urgently needed but are not within reach because some of the most critical virulence strategies of these pathogens are not understood 8 . The pathogenic potential of prominent healthcare-associated (HA)-MRSA and recently emerged livestock-associated (LA)-MRSA strains is thought to rely on particularly effective immune evasion strategies, whereas communityassociated (CA)-MRSA strains often produce more aggressive toxins 1,2 . Most humans have high overall levels of antibodies against S. aureus as a consequence of preceding infections, but antibody titres differ strongly for specific antigens and are often not protective in immunocompromised patients, for reasons that are not clear 3 . A large percentage of human antibodies against S. aureus is directed against WTA 5,9,10 , which is largely invariant. However, some S. aureus lineages produce altered WTA, which modulates, for instance, phage susceptibility 7,11 .To investigate whether ...
Many Staphylococcus aureus have lost a major genetic barrier against phage infection, termed clustered regularly interspaced palindromic repeats (CRISPR/cas). Hence, S. aureus strains frequently exchange genetic material via phage-mediated horizontal gene transfer events, but, in turn, are vulnerable in particular to lytic phages. Here, a novel strategy of S. aureus is described, which protects S. aureus against the lytic activity of Podoviridae, a unique family of staphylococcal lytic phages with short, non-contractile tails. Unlike most staphylococcal phages, Podoviridae require a precise wall teichoic acid (WTA) glycosylation pattern for infection. Notably, TarM-mediated WTA α-O-GlcNAcylation prevents infection of Podoviridae while TarS-mediated WTA β-O-GlcNAcylation is required for S. aureus susceptibility to podoviruses. Tracking the evolution of TarM revealed an ancient origin in other staphylococci and vertical inheritance during S. aureus evolution. However, certain phylogenetic branches have lost tarM during evolution, which rendered them podovirus-susceptible. Accordingly, lack of tarM correlates with podovirus susceptibility and can be converted into a podovirus-resistant phenotype upon ectopic expression of tarM indicating that a “glyco-switch” of WTA O-GlcNAcylation can prevent the infection by certain staphylococcal phages. Since lytic staphylococcal phages are considered as anti-S. aureus agents, these data may help to establish valuable strategies for treatment of infections.
Most Staphylococcus aureus isolates carry multiple bacteriophages in their genome, which provide the pathogen with traits important for niche adaptation. Such temperate S. aureus phages often encode a variety of accessory factors that influence virulence, immune evasion and host preference of the bacterial lysogen. Moreover, transducing phages are primary vehicles for horizontal gene transfer. Wall teichoic acid (WTA) acts as a common phage receptor for staphylococcal phages and structural variations of WTA govern phage-host specificity thereby shaping gene transfer across clonal lineages and even species. Thus, bacteriophages are central for the success of S. aureus as a human pathogen.
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