Complement Factor H-Binding Protein, a Putative Virulence Determinant of Borrelia hermsii, Is an Antigenic Target for Protective B1b Lymphocytes

Abstract

Vaccination is the most effective way to control infectious diseases. A variety of microbial pathogens use antigenic variation, an immune evasion strategy that poses a challenge for vaccine development. To understand protective immune responses against such pathogens, we have been studying Borrelia hermsii, a bacterium that causes recurrent bacteremia due to antigenic variation. An IgM response is necessary and sufficient to control B. hermsii infection. We have recently found a selective expansion of B1b cells concurrent with the resolution of B. hermsii bacteremia. B1b cells from convalescent but not naive mice confer long-lasting immunity, but the Ag(s) driving the protective IgM responses is unknown. Herein we demonstrate that convalescent B1b cell-derived IgM recognizes complement factor H-binding protein (FhbA), a B. hermsii outer-surface protein and putative virulence factor that does not undergo antigenic variation and is expressed by all clinical isolates. A progressive increase in the IgM response to FhbA correlated with the kinetics of B1b cell expansion, diminished the severity of bacteremic episodes, and led to the eventual resolution of the infection. These data indicate that FhbA is a specific target for protective B1b cell responses. Ags recognized by B1b cells may be considered as an important component in vaccination strategies.

IL-7–Dependent B Lymphocytes Are Essential for the Anti-polysaccharide Response and Protective Immunity toStreptococcus pneumoniae

“…However, natural Abs do not play a critical role in clearance of Borrelia hermsii, a bacterial pathogen, whose elimination requires B1b cells (22). Moreover, natural Abs do not recognize FhbA, a B. hermsii Ag target for B1b cells (22), suggesting that B1b cells produced early in life do not contribute significantly to the anti-B. hermsii response (18,56).…”

“…Although natural Abs are generally of low affinity to self or evolutionarily conserved Ags (52), they have been shown to play a role in the early control of pathogen burden in bacterial and viral infection models (51,(53)(54)(55). However, natural Abs do not play a critical role in clearance of Borrelia hermsii, a bacterial pathogen, whose elimination requires B1b cells (22). Moreover, natural Abs do not recognize FhbA, a B. hermsii Ag target for B1b cells (22), suggesting that B1b cells produced early in life do not contribute significantly to the anti-B.…”

“…Indeed, reconstitution of immunodeficient Rag1 2/2 mice with various B cell subsets demonstrated that B1b cells generate the majority of the IgM and IgG3 responses to PPS type 3 (PPS3) and NP-Ficoll (5,21). Although a variety of Ags that drive the TI B1b cell response have been identified to date (5,19,(21)(22)(23), the developmental origin of Ag-specific B1b cells is unknown. The ontogeny of B cells early and late in life originates from fetal liver and bone marrow lymphopoeisis, respectively (24).…”

The Loss and Gain of Marginal Zone and Peritoneal B Cells Is Different in Response to Relapsing Fever and Lyme Disease Borrelia

“…We also found persisting immunity to B. crocidurae, as mice were resistant to re-challenge more than 2 mo after the initial infection (data not shown). B1b cells provide inducible T cell-independent memory and long-lasting protection against B. hermsii, and complement factor H-binding protein was recently identified as a target Ag for this protective response (5,20).…”

“…A prompt Ab response targeting the dominant variable surface Ag results in the rapid clearance of the spirochetes from the bloodstream. Meanwhile, an Ab response to an outer surface protein that does not undergo antigenic variation, the complement factor H-binding protein, is proposed to ultimately defeat the immune evasion tactics used by Borrelia hermsii, a relapsing fever species (5). Although Ab responses are also clearly protective against B. burgdorferi, they are outmaneuvered by numerous evasion strategies.…”