December 5, 2023

The complexity of phagocytosis resistance is emphasized by the finding that the genetic background of a strain influences M protein function (57, 58)

The complexity of phagocytosis resistance is emphasized by the finding that the genetic background of a strain influences M protein function (57, 58). blood (5). Here, we analyze the mechanism by which M protein allows to evade phagocytosis. is usually a gram-positive bacterium causing a variety of diseases, including acute pharyngitis, skin infections, a toxic shock syndrome, and rheumatic fever (6). The surface M protein of plays a key role in conferring phagocytosis resistance (5), but the hyaluronic acid capsule expressed by many strains also makes an important contribution (7). The M protein is usually a dimeric coiled coil with an NH2-terminal hypervariable region (HVR) that exhibits extensive sequence variability between strains, allowing classification of clinical isolates into 120 different M types (8). Antibodies directed against the HVR block the L755507 antiphagocytic property of M protein, implying that this HVR plays an important role in conferring phagocytosis resistance (5, 9, 10). However, the extreme sequence variability in the Mouse monoclonal to ELK1 HVR has made it difficult to explain L755507 how this region can have the specific function to inhibit phagocytosis. To explain this apparent paradox, it has been suggested that this HVR causes repulsion of L755507 phagocytes by having a negative charge, a mechanism that might allow extensive sequence variability (5, 11). In agreement with this hypothesis, M protein is known to inhibit binding of to nonactivated phagocytes (12). However, evidence has accumulated that this HVR also has a specific ligand-binding function. In particular, the HVRs of many M proteins specifically bind the human complement regulator C4b-binding protein (C4BP), a 570-kD plasma protein that inhibits the classical pathway of complement activation by accelerating the decay of the C3 convertase of this pathway and by acting as a cofactor to factor I in the degradation of C4b (13C17). Importantly, 50% of clinical isolates bind C4BP, and all available evidence indicates that this house is due to expression of an M protein in which the HVR binds C4BP (13C15, 18). In a previous paper, we showed that binding of C4BP to the HVR can partially explain the ability of an M protein to confer phagocytosis resistance (19), but the mechanism by which the M protein confers full resistance to phagocytosis remained unclear. Moreover, the contribution of bacteria-bound C4BP to phagocytosis resistance was puzzling, because C4BP L755507 specifically down-regulates the classical pathway of complement activation (16, 17), which is commonly believed not to be activated under nonimmune conditions. The data reported here provide explanations for both of these problems. Our studies were focused on the M22 protein (19), which has properties typical of many M proteins and is commonly expressed by clinical isolates of (20). In addition to an HVR that binds C4BP, the M22 protein has an adjacent semivariable region that binds human IgA-Fc, another common M protein ligand (21C24). Because the IgA-binding region varies in sequence between different M proteins (23), we hypothesized that this region is usually a target for protective antibodies and contributes to phagocytosis resistance. The studies described here show that this C4BP- and IgA-binding regions of the M22 protein cooperate in conferring phagocytosis resistance and can fully account for the antiphagocytic property of M22. Moreover, bacteria-bound C4BP down-regulated complement activation, that occurred via the classical pathway even under nonimmune conditions, providing an explanation for the ability of bound C4BP to inhibit phagocytosis. Thus, a coherent picture is now emerging of the mechanisms, by which M22 and related M proteins confer phagocytosis resistance. Materials and Methods Bacterial Strains. AL168 is L755507 an OF+ strain of serotype M22. Like other OF+ strains of genes (25). The strain referred to here as M22.