Characterization of Recombinant B. abortus Strain RB51SOD Toward Understanding the Uncorrelated Innate and Adaptive Immune Responses Induced byRB51SOD Compared to Its Parent Vaccine Strain RB51

Zhu, Jingde; Larson, Christopher; Ramaker, Megan A.; Quandt, Kimberly; Wendte, Jered M.; Ku, Kimberly; Fang, Chen; Jourdian, George W.; Vemulapalli, Ramesh; Schurig, Gerhardt G.; He, Yongqun

doi:10.3389/fcimb.2011.00010

Cited by 6 publications

(9 citation statements)

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“…One possible explanation is that Brucella vaccines may not effectively penetrate into mucosal physical barriers ( e.g ., nose). Therefore, Brucella antigens cannot efficiently be presented to the antigen presenting cells, including dendritic cells and macrophages [39]. …”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates

et al. 2013

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BackgroundVaccine protection investigation includes three processes: vaccination, pathogen challenge, and vaccine protection efficacy assessment. Many variables can affect the results of vaccine protection. Brucella, a genus of facultative intracellular bacteria, is the etiologic agent of brucellosis in humans and multiple animal species. Extensive research has been conducted in developing effective live attenuated Brucella vaccines. We hypothesized that some variables play a more important role than others in determining vaccine protective efficacy. Using Brucella vaccines and vaccine candidates as study models, this hypothesis was tested by meta-analysis of Brucella vaccine studies reported in the literature.ResultsNineteen variables related to vaccine-induced protection of mice against infection with virulent brucellae were selected based on modeling investigation of the vaccine protection processes. The variable "vaccine protection efficacy" was set as a dependent variable while the other eighteen were set as independent variables. Discrete or continuous values were collected from papers for each variable of each data set. In total, 401 experimental groups were manually annotated from 74 peer-reviewed publications containing mouse protection data for live attenuated Brucella vaccines or vaccine candidates. Our ANOVA analysis indicated that nine variables contributed significantly (P-value < 0.05) to Brucella vaccine protection efficacy: vaccine strain, vaccination host (mouse) strain, vaccination dose, vaccination route, challenge pathogen strain, challenge route, challenge-killing interval, colony forming units (CFUs) in mouse spleen, and CFU reduction compared to control group. The other 10 variables (e.g., mouse age, vaccination-challenge interval, and challenge dose) were not found to be statistically significant (P-value > 0.05). The protection level of RB51 was sacrificed when the values of several variables (e.g., vaccination route, vaccine viability, and challenge pathogen strain) change. It is suggestive that it is difficult to protect against aerosol challenge. Somewhat counter-intuitively, our results indicate that intraperitoneal and subcutaneous vaccinations are much more effective to protect against aerosol Brucella challenge than intranasal vaccination.ConclusionsLiterature meta-analysis identified variables that significantly contribute to Brucella vaccine protection efficacy. The results obtained provide critical information for rational vaccine study design. Literature meta-analysis is generic and can be applied to analyze variables critical for vaccine protection against other infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates

et al. 2013

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“…Zhu, et al has reported that overexpressed Cu-Zn SOD protein by Brucella vaccine strain RB51 damages the integrity of the outer membrane of RB51 Brucella cells [ 4 ]. To determine if secretion of Cu-Zn SOD protein in B. abortus 2308 results from leakage of damaged outer membranes, we investigated membrane integrity with transmission electron microscope analysis of wild type B. abortus 2308 and 2308 overexpressing Cu-Zn SOD.…”

Section: Resultsmentioning

confidence: 99%

“…Another important finding of this study is that overexpressed Cu-Zn SOD inhibits B. abortus intracellular growth via suppressing the activity of the small GTpase protein Sar1. Previous study showed that macrophages infected with Brucella RB51 Cu-Zn SOD strain exhibited a significantly lower number of surviving cells than RB51 strains [ 4 ]. However, the underlying mechanism remains elusive.…”

Section: Discussionmentioning

confidence: 99%

“…B. abortus strain 2308 or the strain overexpressed Cu-Zn SOD was cultured in TSB to an OD600 of 1.0 (or to the late log phase). The rest procedures were performed as previous study described [ 4 ]. Briefly, bacteria were fixed in an ice-cold solution of 4% formaldehyde and 2.5% glutaraldehyde.…”

Section: Methodsmentioning

confidence: 99%

“…Intramuscular administration of a plasmid vector coding for Cu-Zn SOD confers protection in mice and strong immune responses in calves [ 3 ]. More importantly, overexpression of Cu-Zn SOD in a RB51 vaccine strain (RB51SOD strain) significantly increases its vaccine efficacy against B. abortus challenge and decreases its survival rate in macrophages [ 4 ]. However, the mechanism by which overexpressed Cu-Zn SOD mediates bacterial intracellular replication remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Cu-Zn SOD in Brucella abortus suppresses bacterial intracellular replication via down-regulation of Sar1 activity

Liu

Zhou²,

Yang

et al. 2018

Oncotarget

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Brucella Cu-Zn superoxide dismutase (Cu-Zn SOD) is a periplasmic protein, and immunization of mice with recombinant Cu-Zn SOD protein confers protection against Brucella abortus infection. However, the role of Cu-Zn SOD during the process of Brucella infection remains unknown. Here, we report that Cu-Zn SOD is secreted into culture medium and is translocated into host cells independent of type IV secretion systems (T4SS). Furthermore, co-immunoprecipitation and immunofluorescence studies reveal that Brucella abortus Cu-Zn SOD interacts with the small GTPase Sar1. Overexpression of Cu-Zn SOD in Brucella abortus inhibits bacterial intracellular growth by abolishing Sar1 activity in a manner independent of reactive oxygen species (ROS) production.

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Caspase-2-Dependent Dendritic Cell Death, Maturation, and Priming of T Cells in Response to Brucella abortus Infection

2012

PLoS ONE

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Smooth virulent Brucella abortus strain 2308 (S2308) causes zoonotic brucellosis in cattle and humans. Rough B. abortus strain RB51, derived from S2308, is a live attenuated cattle vaccine strain licensed in the USA and many other countries. Our previous report indicated that RB51, but not S2308, induces a caspase-2-dependent apoptotic and necrotic macrophage cell death. Dendritic cells (DCs) are professional antigen presenting cells critical for bridging innate and adaptive immune responses. In contrast to Brucella-infected macrophages, here we report that S2308 induced higher levels of apoptotic and necrotic cell death in wild type bone marrow-derived DCs (WT BMDCs) than RB51. The RB51 and S2308-induced BMDC cell death was regulated by caspase-2, indicated by the minimal cell death in RB51 and S2308-infected BMDCs isolated from caspase-2 knockout mice (Casp2KO BMDCs). More S2308 bacteria were taken up by Casp2KO BMDCs than wild type BMDCs. Higher levels of S2308 and RB51 cells were found in infected Casp2KO BMDCs compared to infected WT BMDCs at different time points. RB51-infected wild type BMDCs were mature and activated as shown by significantly up-regulated expression of CD40, CD80, CD86, MHC-I, and MHC-II. RB51 induced the production of cytokines TNF-α, IL-6, IFN-γ and IL12/IL23p40 in infected BMDCs. RB51-infected WT BMDCs also stimulated the proliferation of CD4+ and CD8+ T cells compared to uninfected WT BMDCs. However, the maturation, activation, and cytokine secretion are significantly impaired in Casp2KO BMDCs infected with RB51 or Salmonella (control). S2308-infected WT and Casp2KO BMDCs were not activated and could not induce cytokine production. These results demonstrated that virulent smooth strain S2308 induced more apoptotic and necrotic dendritic cell death than live attenuated rough vaccine strain RB51; however, RB51, but not its parent strain S2308, induced caspase-2-mediated DC maturation, cytokine production, antigen presentation, and T cell priming.

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Characterization of Recombinant B. abortus Strain RB51SOD Toward Understanding the Uncorrelated Innate and Adaptive Immune Responses Induced byRB51SOD Compared to Its Parent Vaccine Strain RB51

Cited by 6 publications

References 61 publications

Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates

Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates

Overexpression of Cu-Zn SOD in Brucella abortus suppresses bacterial intracellular replication via down-regulation of Sar1 activity

Caspase-2-Dependent Dendritic Cell Death, Maturation, and Priming of T Cells in Response to Brucella abortus Infection

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