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Group A streptococci induce high-affinity M protein-fibronectin interaction when specific human antibodies are bound

Group A streptococcus (GAS) is a highly adapted, humanspecific pathogen that is known to manipulate the immune system through various mechanisms. GAS’ M protein constitutes a primary target of the immune system due to its spatial configuration and dominance on the bacterial surface. Antibody responses targeting the M protein have been shown to favor the conserved C region. Such antibodies circumvent antigenic escape and efficiently bind to various M types. The ability of GAS to bind to fibronectin (Fn), a high molecular weight glycoprotein of the extracellular matrix, has long been known to be essential for the pathogen’s evolutionary success and fitness. However, some strains lack the ability to efficiently bind Fn. Instead, they have been found to inefficiently bind Fn via the M protein A-B domains. Here, we show that human antibodies can induce a high-affinity Fn-binding state in M proteins, likely by enhancing the weak A-B domain binding. The antibodies bind to a conserved region of M proteins, and the high-affinity binding only occurs on the individual M proteins with bound specific antibodies. By allowing the binding of antibodies to a certain region in M, and thereby enhancing Fn-binding, GAS exploits the human humoral immune response to efficiently bind Fn without needing to waste energy on the production of additional proteins – potentially giving such strains an evolutionary advantage.