Protective Immunity Elicited by Oral Immunization of Mice with Salmonella enterica Serovar Typhimurium Braun Lipoprotein (Lpp) and Acetyltransferase (MsbB) Mutants

Abstract

We evaluated the extent of attenuation and immunogenicity of the ΔlppAB and ΔlppAB ΔmsbB mutants of Salmonella enterica serovar Typhimurium when delivered to mice by the oral route. These mutants were deleted either for the Braun lipoprotein genes (lppA and lppB) or in combination with the msbB gene, which encodes an acetyltransferase required for lipid A modification of lipopolysaccharide. Both the mutants were attenuated (100% animal survival) and triggered robust innate and adaptive immune responses. Comparable levels of IgG and its isotypes were produced in mice infected with wild-type (WT) S. typhimurium or its aforementioned mutant strains. The ΔlppAB ΔmsbB mutant-immunized animals resulted in the production of higher levels of fecal IgA and serum cytokines during later stages of vaccination (adaptive response). A significant production of interleukin-6 from T-cells was also noted in the ΔlppAB ΔmsbB mutant-immunized mice when compared to that of the ΔlppAB mutant. On the other hand, IL-17A production was significantly more in the serum of ΔlppAB mutant-immunized mice (innate response) with a stronger splenic T-cell proliferative and tumor-necrosis factor-α production. Based on 2-dimensional gel analysis, alterations in the levels of several proteins were observed in both the mutant strains when compared to that in WT S. typhimurium and could be associated with the higher immunogenicity of the mutants. Finally, both ΔlppAB and ΔlppAB ΔmsbB mutants provided complete protection to immunized mice against a lethal oral challenge dose of WT S. typhimurium. Thus, these mutants may serve as excellent vaccine candidates and also provide a platform for delivering heterologous antigens.

Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models

“…Moreover, in a mouse that died from infection, there was a marked thrombosis in the spleen and liver, suggesting that this correlates with disease severity. Vaccination can reduce the level of thrombosis induced (109). Furthermore, a model to study Salmonella -associated meningitis demonstrated that this infection can induce thrombosis in the brain (110).…”

Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

“…Similarly, in Salmonella enterica serovar Typhimurium, the inactivation of two murein lipoproteins caused a very significant impairment of virulence, in terms of a drastic reduction of invasion/cytotoxicity in cell culture and of mortality in murine models (39) (Table 1). And again, similarly to yersiniae, S. enterica serovar Typhimurium mutants with mutations in some PGN structural elements, such as Braun's lipoprotein, have recently been tested as vaccine candidates, with promising results (40). Interestingly, and still related to Braun's lipoprotein, Hernández and colleagues have shown in Salmonella that the effects of bile could induce the selection of some modifications leading to an increased resistance to this natural detergent (41).…”

HU-Lacking Mutants of Salmonella enterica Enteritidis Are Highly Attenuated and Can Induce Protection in Murine Model of Infection

“…IgA production is important as the first line of defense in intestinal infection. Moreover, Erova et al (2016) showed, using a different vaccination strategy, that the efficiency of IgA against salmonellosis is associated with its sustained production in animal models following vaccination, demonstrating that it also participates in adaptive immunity. We observed a significant increase in IFN-γ levels in animals receiving only one dose of attenuated PT4Δ hupAB , and this profile was sustained at 49 days later after infection.…”

“…Hence, live-attenuated vaccines are an attractive vaccine platform as these vaccines can confer long-lasting protection to prevent invasive Salmonella serovars. Moreover, these vaccines are inexpensive and easy-to-implement ( Erova et al, 2016 ). Vaccination protocols for this platform have been tested in both humans ( Maclennan et al, 2014 ) and animals ( Haneda et al, 2011 ; Desin et al, 2013 ).…”