Methicillin-Resistant Staphylococcus aureus Alters Cell Wall Glycosylation to evade Immunity
The bacterium Staphylococcus aureus is a frequent cause of difficult-to-treat human, infections. Strains of the bacterium termed methicillin-resistant S. aureus (MRSA) cause both hospital- and community-acquired infections around the globe Most humans have antibodies against S. aureus, but these are highly variable and often not protective in immunocompromised patients. A large percentage of human antibodies against S. aureus target wall teichoic acid (WTA). This is a ribitol-phosphate (RboP) surface polymer modified with N-acetylglucosamine (GlcNAc). which forms a highly hydrated, gel-like material that fills much of the space between peptidoglycan strands. It is currently unknown whether the immune evasion capacities of MRSA are due to the variation of dominant surface epitopes such as those associated with WTA. The results presented in the article show that a considerable proportion of the prominent healthcare-associated and livestock-associated MRSA clones contain prophages that encode an alternative WTA glycosyltransferase.
The study of the genome sequences of MRSA strains revealed genes encoding enzymes that modify WTA. MRSA strains encode an enzyme called TarP that catalyzes the addition of GlcNAc to d-ribitol phosphate at a particular carbon atom (known as C3) in the ribitol. Normally, GlcNAc is added at a different position, the C4 carbon, by the action of a related enzyme called TarS. 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, mouse 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 defenses. High-resolution structural analyses of TarP bound to WTA components and uridine diphosphate GlcNAc (UDPGlcNAc) explain the mechanism of altered RboP glycosylation and form a template for targeted inhibition of TarP.