Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague

Abstract

The generation of adaptive immunity by vaccination is usually a prolonged process that requires multiple dosing over several months. Hence, vaccines are administered for disease prevention a relatively long time prior to possible infection as opposed to post-exposure prophylaxis, which typically requires rapid intervention such as antibiotic therapy. The emergence of pathogens resistant to common antibiotic treatments has prompted the search for alternative therapeutic strategies. We previously demonstrated that vaccination of mice with the F1 capsular antigen of Yersinia pestis elicits specific and effective yet, unexpectedly, rapid anti-plague immunity. Here, we show by applying genetic and immunological approaches that the F1 antigen is targeted by peritoneal innate-like B1b cells that generate a prompt T-independent (TI) anti-F1 humoral response. The rapid F1-mediated defense response was diminished in Xid (Btkm) mice in which B1 cell numbers and activity are limited. Binding of fluorophore-labeled F1 to peritoneal B1b cells was detected as soon as 6 h post vaccination, emphasizing the high speed of this process. By assessing the ability to achieve rapid immunity with monomerized F1, we show that the natural polymeric structure of F1 is essential for (i) rapid association with peritoneal B1b cells, (ii) early induction of anti-F1 titers and (iii) rapid TI immunity in the mouse model of bubonic plague. These observations shed new light on the potential of novel as well as well-known protective antigens in generating rapid immunity and could be implemented in the rational design of future vaccines.

A Recombinant Attenuated Yersinia pseudotuberculosis Vaccine Delivering a Y. pestis YopE Nt138 -LcrV Fusion Elicits Broad Protection against Plague and Yersiniosis in Mice

“…In addition, studies reported that IgM could compensate on mucosal surfaces for the lack of IgA (46,47) and facilitate the removal of foreign pathogens due to its efficient agglutination (48). Moreover, IgM-mediated protection was reported against infection with different pathogens: Haemophilus influenzae (49), Ehrlichia muris (50), Borrelia hermsii (51), Streptococcus pneumoniae (52), and Y. pestis (53). So far, it is unknown whether IgM induced by 10069(pYA5199) immunization and deposited on respiratory mucosal surfaces in mice could correlate with protection against pneumonic plague.…”

Vaccine Potential of a Recombinant Bivalent Fusion Protein LcrV-HSP70 Against Plague and Yersiniosis

“…In the recent past, many reports have been published on F1/LcrV based vaccine formulations. The F1/LcrV vaccine antigens adjuvanted with alum induce robust humoral immune responses and impart 100% protection in a mouse model (16,(21)(22)(23)(24) with no side effects in humans (25). F1/LcrV antigen-based vaccine formulations protect cynomolgus macaques against aerosolized Y. pestis but failed to protect African Green monkeys (26,27).…”

Protection Elicited by Attenuated Live Yersinia pestis Vaccine Strains against Lethal Infection with Virulent Y. pestis

“…The absence of capsule in the C12 vaccine strain potentially exposed more antigens to the immune system than was the case with the F1-positive strain. F1 is known to induce primarily a T-cell independent humoral immunity [ 32 , 126 , 127 ], except perhaps when subunit antigens are delivered by a mucosal route, such as orally or intranasally [ 33 , 128 ]. Furthermore, the efficacy and ELISA data implied that the antibody response to F1 played a more significant role in protection, as described above.…”