Abstract
ABSTRACTAntibodies acquired after vaccination or natural infection with Gram-negative bacteria, such as invasive Salmonella enterica serovar Typhimurium, can protect against disease. Immunization with naturally shed outer membrane vesicles from Gram-negative bacteria is being studied for its potential to protect against many infections, since antigens within vesicles maintain their natural conformation and orientation. Shedding can be enhanced through genetic modification, and the resulting particles, generalized modules for membrane antigens (GMMA), not only offer potential as vaccines but also can facilitate the study of B-cell responses to bacterial antigens. Here we show that the response to immunization with GMMA from S. Typhimurium (STmGMMA) provides B-cell-dependent protection and induces antibodies to two immunodominant antigens, lipopolysaccharide (LPS) and porins. Antibodies to LPS O antigen (O-Ag) markedly enhance protection in the spleen, but this effect is less marked in the liver. Strikingly, IgG responses to LPS and porins develop with distinct kinetics. In the first week after immunization, there is a dramatic T-cell-independent B1b-cell-associated induction of all IgG isotypes, except IgG1, to porins but not to LPS. In contrast, production of IgG1 to either antigen was delayed and T cell dependent. Nevertheless, after 1 month, cells in the bone marrow secreting IgG against porins or LPS were present at a similar frequency. Unexpectedly, immunization with O-Ag-deficient STmGMMA did not substantially enhance the anti-porin response. Therefore, IgG switching to all antigens does not develop synchronously within the same complex and so the rate of IgG switching to a single component does not necessarily reflect its frequency within the antigenic complex.
Highlights
Citation Schager AE, Dominguez-Medina CC, Necchi F, Micoli F, Goh YS, Goodall M, FloresLangarica A, Bobat S, Cook CNL, Arcuri M, Marini A, King LDW, Morris FC, Anderson G, Toellner K-M, Henderson IR, López-Macías C, MacLennan CA, Cunningham AF. 2018
After immunization of C57BL/6 mice intraperitoneally (i.p.) with 1 g of STmGMMA, there was a rapid induction of IgM and IgG, with both detectable by day 4, and while IgM titers remained relatively stable, IgG titers continued rising over the following weeks (Fig. 1B)
Experiments where nonimmunized mice were infected for 24 h with bacteria that had been opsonized with serum from nonimmunized or STmGMMA-immunized mice showed that the presence of anti-STmGMMA Ab was sufficient to reduce bacterial colonization of the spleen and liver (Fig. 1D)
Summary
Citation Schager AE, Dominguez-Medina CC, Necchi F, Micoli F, Goh YS, Goodall M, FloresLangarica A, Bobat S, Cook CNL, Arcuri M, Marini A, King LDW, Morris FC, Anderson G, Toellner K-M, Henderson IR, López-Macías C, MacLennan CA, Cunningham AF. 2018. Key advantages of NOMVs include their potential safety for use in humans [1], enrichment for surface antigens that are often recognized by B cells, and maintenance of these antigens in their natural conformation and orientation [2]. These nano-sized, nonviable antigens can be used in immunocompromised individuals and overcome the potential risks of infection associated with the use of live, attenuated vaccines in such populations. While antibodies to LPS and porins are detectable after natural infection, little is known about the relative kinetics of their induction, in the context of OMVs and GMMA. These data show that B-cell responses to all antigens do not develop in parallel within the same GMMA antigenic complex and that the extent of the early IgG response does not necessarily reflect the relative abundance of an antigen within a complex
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