Terminal Deoxynucleotidyl Transferase Is Not Required for Antibody Response to Polysaccharide Vaccines against Streptococcus pneumoniae and Salmonella enterica Serovar Typhi

Abstract

B cell antigen receptor (BCR) diversity increases by several orders of magnitude due to the action of terminal deoxynucleotidyl transferase (TdT) during V(D)J recombination. Unlike adults, infants have limited BCR diversity, in part due to reduced expression of TdT. Since human infants and young mice respond poorly to polysaccharide vaccines, such as the pneumococcal polysaccharide vaccine Pneumovax23 and Vi polysaccharide (ViPS) of serovar Typhi, we tested the contribution of TdT-mediated BCR diversity in response to these vaccines. We found that TdT and TdT mice generated comparable antibody responses to Pneumovax23 and survived challenge. Moreover, passive immunization of B cell-deficient mice with serum from Pneumovax23-immunized TdT or TdT mice conferred protection. TdT and TdT mice generated comparable levels of anti-ViPS antibodies and antibody-dependent, complement-mediated bactericidal activity against Typhi To test the protective immunity conferred by ViPS immunization , TdT and TdT mice were challenged with a chimeric serovar Typhimurium strain expressing ViPS, since mice are nonpermissive hosts for Typhi infection. Compared to their unimmunized counterparts, immunized TdT and TdT mice challenged with ViPS-expressing Typhimurium exhibited a significant reduction in the bacterial burden and liver pathology. These data suggest that the impaired antibody response to the Pneumovax23 and ViPS vaccines in the young is not due to limited TdT-mediated BCR diversification.

Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection

“…This strain of S. Typhimurium, referred to as RC60, was shown to exhibit cell surface and other characteristics of S. Typhi 4 . Using the S. Typhimurium strain RC60, we were able to identify several aspects of the anti-ViPS antibody repertoire required for protective immunity in vivo 35 , 43 , 52 . Thus, the use of S. Typhimurium as a “surrogate” model to understand certain virulence mechanisms of S. Typhi has been justified.…”

“…We also perform serum bactericidal assay using anti- S . Typhi human IgG (Lot R1, 2011; U.S. Food and Drug Administration, Silver Spring, MD) as described 35 , 52 , 63 . Blood samples were obtained 0-, 7-, 14- or 21-days following immunization and stored at − 20 °C.…”

Collaborative Cross mice are permissive to Salmonella enterica serovar Typhi infection

“…This strain of S. Typhimurium, referred to as RC60, was shown to exhibit cell surface and other characteristics of S. Typhi 4 . Using the S. Typhimurium strain RC60, we were able to identify several aspects of the anti-ViPS antibody repertoire required for protective immunity in vivo 34,43,52 . Thus, the use of S. Typhimurium as a "surrogate" model to understand certain virulence mechanisms of S. Typhi has been justified.…”

Collaborative Cross mice are permissive to Salmonella enterica serovar Typhi infection

“…This strain of S. Typhimurium, referred to as RC60, was shown to exhibit cell surface and other characteristics of S. Typhi 4 . Using the S. Typhimurium strain RC60, we were able to identify several aspects of the anti-ViPS antibody repertoire required for protective immunity in vivo 35,42,51 . Thus, the use of S. Typhimurium as a "surrogate" model to understand certain virulence mechanisms of S. Typhi has been justi ed.…”