Genomic analysis of the original Elberg <i>Brucella melitensis</i> Rev.1 vaccine strain reveals insights into virulence attenuation

Salmon‐Divon, Mali; Yeheskel, Adva; Kornspan, David

doi:10.1080/21505594.2018.1511677

Cited by 10 publications

(5 citation statements)

References 69 publications

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“…On this basis, the high attenuation of Rev1 wzm should have led to failed efficacy; however, and, unpredictably, Rev1 wzm (but not Rev1 wzt) triggered a splenomegaly associated with a particular Th1 cytokine balance, as well as to a protective efficacy against virulent challenges. Besides the genetic and phenotypic divergences described between the Rev1 and 16M parentals related to virulence attenuation (Issa and Ashhab, 2016;Salmon-Divon et al, 2018Kornspan et al, 2020), we have now described additional differences in genetic transcription, antigenicity evidenced by Western blot, and susceptibility to antibiotics and environmental stress factors. Indeed, when wzm/wzt mutations were applied to other brucellae (Wang et al, 2014a;Grilló et al, 2017;Aragón-Aranda et al, 2020;Lalsiamthara et al, 2020), neither mutant was as immunogenic as Rev1 wzm.…”

Section: The Impact Of the Rev1 Background On Rev1 Wzm Vaccine Proper...mentioning

confidence: 69%

Brucella melitensis Wzm/Wzt System: Changes in the Bacterial Envelope Lead to Improved Rev1Δwzm Vaccine Properties

et al. 2022

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The lipopolysaccharide (LPS) O-polysaccharide (O-PS) is the main virulence factor in Brucella. After synthesis in the cytoplasmic membrane, O-PS is exported to the periplasm by the Wzm/Wzt system, where it is assembled into a LPS. This translocation also engages a bactoprenol carrier required for further biosynthesis pathways, such as cell wall biogenesis. Targeting O-PS export by blockage holds great potential for vaccine development, but little is known about the biological implications of each Wzm/Wzt moiety. To improve this knowledge and to elucidate its potential application as a vaccine, we constructed and studied wzm/wzt single- and double-deletion mutants, using the attenuated strain Brucella melitensis Rev1 as the parental strain. This allowed us to describe the composition of Brucella peptidoglycan for the first time. We observed that these mutants lack external O-PS yet trigger changes in genetic transcription and in phenotypic properties associated with the outer membrane and cell wall. Both mutants are highly attenuated; unexpectedly, Rev1Δwzm also excels as an immunogenic and effective vaccine against B. melitensis and Brucella ovis in mice, revealing that low persistence is not at odds with efficacy. Rev1Δwzm is attenuated in BeWo trophoblasts, does not infect mouse placentas, and is safe in pregnant ewes. Overall, these attributes and the minimal serological interference induced in sheep make Rev1Δwzm a highly promising vaccine candidate.

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Section: The Impact Of the Rev1 Background On Rev1 Wzm Vaccine Proper...mentioning

confidence: 69%

Brucella melitensis Wzm/Wzt System: Changes in the Bacterial Envelope Lead to Improved Rev1Δwzm Vaccine Properties

et al. 2022

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“…CIIMS-BH-2 and CIIMS-NV-1 had non-synonymous mutation in lysE type translocator family protein. It was reported that B. melitensis Rev.1 had a mutation in lysE type translocator family protein when compared with 16M strain ( Salmon-Divon et al, 2018 ).…”

Section: Core and Accessory Gene Compositionsmentioning

confidence: 99%

Genome Sequencing and Comparative Genomics of Indian Isolates of Brucella melitensis

et al. 2021

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Brucella melitensis causes small ruminant brucellosis and a zoonotic pathogen prevalent worldwide. Whole genome phylogeny of all available B. melitensis genomes (n = 355) revealed that all Indian isolates (n = 16) clustered in the East Mediterranean lineage except the ADMAS-GI strain. Pangenome analysis indicated the presence of limited accessory genomes with few clades showing specific gene presence/absence pattern. A total of 43 virulence genes were predicted in all the Indian strains of B. melitensis except 2007BM-1 (ricA and wbkA are absent). Multilocus sequence typing (MLST) analysis indicated all except one Indian strain (ADMAS-GI) falling into sequence type (ST 8). In comparison with MLST, core genome phylogeny indicated two major clusters (>70% bootstrap support values) among Indian strains. Clusters with <70% bootstrap support values represent strains with diverse evolutionary origins present among animal and human hosts. Genetic relatedness among animal (sheep and goats) and human strains with 100% bootstrap values shows its zoonotic transfer potentiality. SNP-based analysis indicated similar clustering to that of core genome phylogeny. Among the Indian strains, the highest number of unique SNPs (112 SNPs) were shared by a node that involved three strains from Tamil Nadu. The node SNPs involved several peptidase genes like U32, M16 inactive domain protein, clp protease family protein, and M23 family protein and mostly represented non-synonymous (NS) substitutions. Vaccination has been followed in several parts of the world to prevent small ruminant brucellosis but not in India. Comparison of Indian strains with vaccine strains showed that M5 is genetically closer to most of the Indian strains than Rev.1 strain. The presence of most of the virulence genes among all Indian strains and conserved core genome compositions suggest the use of any circulating strain/genotypes for the development of a vaccine candidate for small ruminant brucellosis in India.

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“…Filtered SNPs were subjected to annotation by the SnpEff tool v4.3T [53]. The SnpEff database of the 16 M genome (2002 assembly; [54] and the Rev.1 genome (2018 assembly; [55,56] were built based on GenBank files that were downloaded from NCBI. To validate the detected SNPs and to detect additional mutations that were missed, the analysis was repeated using alignment against the 16M reference genome followed by SNP calling.…”

Section: Snp Detectionmentioning

confidence: 99%

Genomic Analysis of Natural Rough Brucella melitensis Rev.1 Vaccine Strains: Identification and Characterization of Mutations in Key Genes Associated with Bacterial LPS Biosynthesis and Virulence

Kornspan¹,

Lubkovskaia

Mathur

et al. 2020

IJMS

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Brucella species are facultative intracellular bacteria that cause brucellosis, a zoonotic world-wide disease. The live attenuated B. melitensis Rev.1 vaccine strain is widely used for the control of brucellosis in the small ruminant population. However, Rev.1 induces antibodies against the O-polysaccharide (O-PS) of the smooth lipopolysaccharide thus, it is difficult to differentiate between infected and vaccinated animals. Hence, rough Brucella strains lacking the O-PS have been introduced. In the current study, we conducted a comprehensive comparative analysis of the genome sequence of two natural Rev.1 rough strains, isolated from sheep, against that of 24 Rev.1 smooth strains and the virulent reference strain B. melitensis 16M. We identified and characterized eight vital mutations within highly important genes associated with Brucella lipopolysaccharide (LPS) biosynthesis and virulence, which may explain the mechanisms underlying the formation of the Rev.1 rough phenotype and may be used to determine the mechanism underlying virulence attenuation. Further complementation studies aimed to estimate the specific role of these mutations in affecting Brucella morphology and virulence will serve as a basis for the design of new attenuated vaccines for animal immunization against brucellosis.

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Genomic analysis of the original Elberg Brucella melitensis Rev.1 vaccine strain reveals insights into virulence attenuation

Cited by 10 publications

References 69 publications

Brucella melitensis Wzm/Wzt System: Changes in the Bacterial Envelope Lead to Improved Rev1Δwzm Vaccine Properties

Brucella melitensis Wzm/Wzt System: Changes in the Bacterial Envelope Lead to Improved Rev1Δwzm Vaccine Properties

Genome Sequencing and Comparative Genomics of Indian Isolates of Brucella melitensis

Genomic Analysis of Natural Rough Brucella melitensis Rev.1 Vaccine Strains: Identification and Characterization of Mutations in Key Genes Associated with Bacterial LPS Biosynthesis and Virulence

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