Host-specialized fibrinogen-binding by a bacterial surface protein promotes biofilm formation and innate immune evasion

Fibrinogen is an essential part of the blood coagulation cascade and a major component of the extracellular matrix in mammals. The interface between fibrinogen and bacterial pathogens is an important determinant of the outcome of infection. Here, we demonstrate that a canine host-restricted skin pathogen, Staphylococcus pseudintermedius, produces a cell wall-associated protein (SpsL) that has evolved the capacity for high strength binding to canine fibrinogen, with reduced binding to fibrinogen of other mammalian species including humans. Binding occurs via the surface-expressed N2N3 subdomains, of the SpsL A-domain, to multiple sites in the fibrinogen alpha-chain C-domain by a mechanism analogous to the classical dock, lock, and latch binding model. Host-specific binding is dependent on a tandem repeat region of the fibrinogen alpha-chain, a region highly divergent between mammals. Of note, we discovered that the tandem repeat region is also polymorphic in different canine breeds suggesting a potential influence on canine host susceptibility to S. pseudintermedius infection. Importantly, the strong host-specific fibrinogen-binding interaction of SpsL to canine fibrinogen is essential for bacterial aggregation and biofilm formation, and promotes resistance to neutrophil phagocytosis, suggesting a key role for the interaction during pathogenesis. Taken together, we have dissected a bacterial surface protein-ligand interaction resulting from the co-evolution of host and pathogen that promotes host-specific innate immune evasion and may contribute to its host-restricted ecology. Author summary Many bacterial pathogens are specialized for a single host-species and rarely cause infections of other hosts. Our understanding of the bacterial factors underpinning host-specificity are limited. Here we demonstrate that a canine host-restricted bacterial pathogen, Staphylococcus pseudintermedius, produces a surface protein (SpsL) that has the ability to preferentially bind to canine fibrinogen with high strength. This host-specific interaction has evolved via binding to a tandem repeat region of the fibrinogen alpha-chain which is divergent among mammalian species. Importantly, we found that the strong binding interaction with canine fibrinogen promotes bacterial aggregation and biofilm formation as well as inhibiting neutrophil phagocytosis. Our findings reveal the host-adaptive evolution of a key bacterium-host interaction that promotes evasion of the host immune response.