Identification of a Kingella kingae factor H binding protein that is the major determinant of serum resistance.

Kingella kingae is a Gram-negative bacterium that has emerged as a leading cause of invasive disease in children between 6 months and 4 years of age. K. kingae initiates infection by colonizing the oropharynx, then breaches the oropharyngeal epithelium, enters the bloodstream, and disseminates to distant sites to cause disease, including osteomyelitis, septic arthritis, and endocarditis. To survive in the bloodstream and disseminate to sites of invasive disease, K. kingae produces a polysaccharide capsule and an exopolysaccharide that inhibit opsonin deposition and mediate resistance to complement-mediated serum killing. However, elimination of these extracellular polysaccharides only partially reduces K. kingae survival in human serum, suggesting that additional factors contribute to serum resistance. In this study, we found that K. kingae binds human factor H (FH), a negative regulator of the alternative complement pathway. In experiments using rat serum as a source of complement, we observed that K. kingae was able to utilize human FH to resist killing. Introduction of exogenous human FH into the juvenile rat infection model of K. kingae disease enhanced virulence in vivo, demonstrating the importance of FH binding in the pathogenesis of disease. Far-western blot analysis identified a 37-kDa outer membrane protein designated KK02920 that was responsible for FH binding and enhanced virulence in vivo in the presence of human FH. Loss of KK02920 virtually abrogated serum resistance, indicating that KK02920 is the major determinant of K. kingae serum resistance. Additional analysis revealed the presence of KK02920 across a collection of serum-resistant invasive and carrier K. kingae isolates, all of which can utilize human FH to resist complement-mediated killing. This work demonstrates the importance of a complement-regulator binding protein as a major mechanism of serum resistance in an encapsulated organism.