Immune evasion of neutralizing antibodies directed against an essential bacterial surface protein by target hypervariability

Neutralizing antibodies are best characterized in the context of viral infection, where they bind to surface structures on the infectious cell-free virion and prevent host cell receptor binding or membrane fusion. In the context of bacterial infections, neutralizing antibodies are mostly known to operate against secreted toxins, while evidence for activity against the infectious agents themselves is scarce. The bacterial genus Bartonella comprises numerous emerging zoonotic pathogens that cause long-lasting intra-erythrocytic infections in their natural hosts and a broad spectrum of disease manifestations in humans. The targets and mechanisms of the anti-Bartonellaimmune defense are ill-defined and bacterial immune evasion strategies remain elusive. Our study in a model of a natural Bartonella–host relationship revealed that antibody-mediated prevention of bacterial attachment to erythrocytes is sufficient for protection. We identified the essential surface determinant CFA (CAMP-like factor autotransporter) as a major bacterial target of neutralizing antibodies. While immunization with CFA protected against challenge with the homologousBartonella isolate, extensive variability of CFA already at the strain level revealed bacterial immune evasion mechanisms with implications for Bartonella vaccine design. A gene-transfer-agent mediating massive horizontal gene transfer is likely involved in generating the observed antigenic diversity of CFA and possibly other antigenic determinants.