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High-throughput screening for Salmonella avirulent mutants that retain targeting of solid tumors

ABSTRACT: Salmonella has a natural ability to target a wide range of tumors in animal models. However, strains used for cancer therapy have generally been selected only for their avirulence rather than tumor-targeting ability. To select Salmonella strains that are avirulent and yet efficient in tumor-targeting, a necessary criteria for clinical applications, we measured the relative fitness of 41,000 Salmonella Typhimurium transposon insertion mutants growing in mouse models of human prostate cancer and melanoma. Two classes of potentially safe mutants were identified. Class 1 mutants showed reduced fitness in normal tissues and unchanged fitness in tumors (e.g., mutants in htrA, SPI-2, and STM3120). Class 2 mutants showed reduced fitness in tumors and normal tissues (e.g., mutants in aroA and aroD). Class 1 mutants are more suitable for delivery of therapeutics for cancer therapy.

ORGANISM(S): Salmonella enterica Salmonella enterica subsp. enterica serovar Typhimurium str. 14028S

PROVIDER: GSE19609 | GEO | 2010/03/18

SECONDARY ACCESSION(S): PRJNA122445

REPOSITORIES: GEO

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High-throughput screening for Salmonella avirulent mutants that retain targeting of solid tumors

Project description:Salmonella has a natural ability to target a wide range of tumors in animal models. However, strains used for cancer therapy have generally been selected only for their avirulence rather than tumor-targeting ability. To select Salmonella strains that are avirulent and yet efficient in tumor-targeting, a necessary criteria for clinical applications, we measured the relative fitness of 41,000 Salmonella Typhimurium transposon insertion mutants growing in mouse models of human prostate cancer and melanoma. Two classes of potentially safe mutants were identified. Class 1 mutants showed reduced fitness in normal tissues and unchanged fitness in tumors (e.g., mutants in htrA, SPI-2, and STM3120). Class 2 mutants showed reduced fitness in tumors and normal tissues (e.g., mutants in aroA and aroD). Class 1 mutants are more suitable for delivery of therapeutics for cancer therapy. A library of 41,000 Salmonella mutants containing mini-Tn5 transposon insertions was constructed and pooled. The pool was injected into six human prostate (PC3) and six melanoma (MDA-MB-435) tumors growing subcutaneously in nude mice, and injected intravenously into three tumor-free mice. Bacteria were recovered after two days from tumors and spleens, livers, and lungs of tumor-free mice. During in vivo selection, defective mutants in genes contributing to fitness in the selective environment are lost from the pool. Differences in the mutant pool composition before (input pool) and after selection (output pool) can be detected using microarray hybridization: Transposons were used that carry the T7 promoter sequence, allowing the specific amplification of genomic sequences adjacent to each insertion, which are then mapped on the Salmonella genome using a gene microarray

2010-06-18 | E-GEOD-19609 | biostudies-arrayexpress

AroA deficient Salmonella Typhimurium â More than an auxotrophic mutant

Project description:Recombinant attenuated Salmonella are believed to act as powerful live vaccine carrier able to elicit protection against many infectious agents. âaroA exhibits auxotrophy for aromatic amino acids and is commonly used for attenuation. Interestingly, deletion of aroA dramatically increased virulence of the Salmonella. Detailed analyses demonstrate that Salmonellaâs physiology is significantly altered, most likely due to osmotic imbalance and stress. The result is a serious influence of lipid and amino acid turn over, possible increasing sensitivity to penicillin, complement and phagocytic uptake. In addition, in concert with other immunomodulating mutations, the phase of flagella expression is changed. Furthermore, virulence associated genes like arnT or ansB were affected. These alterations could explain the increased virulence. Thus, intravenous application of âaroA Salmonella to mice significantly increased induction of pro-inflammatory cytokines. We also employed such bacteria in therapy against tumors and realized that âaroA strains display an improved anti-tumor activity. The samples of Salmonella Typhimurium Wild type strain and derivates (SF100 (ÎlpxR9 ÎpagL7 ÎpagP8), SF101 (ÎaroA), SF102 (ÎlpxR9 ÎpagL7 ÎpagP8 ÎaroA)) were analyzed by RNA-seq. The control samples were cultivated in the LB medium until the exponential phase. Four biological replicas were pooled in pairs to get two replicas for RNA extraction, library preparation and sequencing. Tumor samples were collected from mice infected with Wt Salmonella and SF102. Bacterial RNA was extracted from single tumors. The tumor samples were split into two technical replicas for sequencing library preparation.

2016-08-09 | E-GEOD-74433 | biostudies-arrayexpress

AroA deficient Salmonella Typhimurium – More than an auxotrophic mutant

Project description:Recombinant attenuated Salmonella are believed to act as powerful live vaccine carrier able to elicit protection against many infectious agents. ∆aroA exhibits auxotrophy for aromatic amino acids and is commonly used for attenuation. Interestingly, deletion of aroA dramatically increased virulence of the Salmonella. Detailed analyses demonstrate that Salmonella’s physiology is significantly altered, most likely due to osmotic imbalance and stress. The result is a serious influence of lipid and amino acid turn over, possible increasing sensitivity to penicillin, complement and phagocytic uptake. In addition, in concert with other immunomodulating mutations, the phase of flagella expression is changed. Furthermore, virulence associated genes like arnT or ansB were affected. These alterations could explain the increased virulence. Thus, intravenous application of ∆aroA Salmonella to mice significantly increased induction of pro-inflammatory cytokines. We also employed such bacteria in therapy against tumors and realized that ∆aroA strains display an improved anti-tumor activity.

2016-08-09 | GSE74433 | GEO

Transcriptional profile of Escherichia coli K12 strain JM109 harboring pUCA1501

Project description:A1501 aroA is a gene derived from Pseudomonas stutzeri A1501, encoding a class II glyphosate-tolerant EPSP synthase. To understand the effect of class II EPSP synthase to E. coli under glyphosate shock, we constructed the class II EPSP synthase-expressing plasmid pUC-A1501. And pUC18 is the empty vector used as a control.

2013-10-15 | GSE46625 | GEO

Transcriptomic analysis of attenuated Salmonella Typhimurium infected chicken primary macrophages

Project description:Salmonella enterica is one of the most important foodborne pathogens that infect a variety of animals and birds. In humans, S. Typhimurium causes gastroenteritis, leading to vomiting, diarrhea, fever, and abdominal cramps. We mainly get infected with Salmonella by ingesting comminated poultry products. Therefore, developing an oral live attenuated vaccine for the poultry industry is our best bet against Salmonella infection. In this article, we investigated the potential of the next generation of Salmonella vaccines. We generated a library of potentially attenuated S. Typhimurium mutants and compared fitness to that of a commercial vaccine. We also investigated the invasion and survival potential of these mutants in chicken macrophages. Our data indicate that although these mutants had no significant growth defects, they were much sensitive to macrophage attack. Analyzing the transcriptome data from infected primary chicken macrophages, we concluded that these mutants elicit a robust immune response by activating several immunoregulatory pathways. Our data also indicates that by combining phoPQ deletion with an already existing cya-crp deletion in MeganVac1, a much stronger immune response can be generated.

2022-05-25 | GSE193063 | GEO

Transcriptional profile of Escherichia coli K12 strain JM109 harboring pUCA1501

2013-10-15 | E-GEOD-46625 | biostudies-arrayexpress

Chlamydia trachomatis HtrA EMS mutants

Project description:C. trachomatis HtrA mutants generated using EMS mutagenesis

| PRJEB9044 | ENA

Salmonella enterica subsp. enterica serovar Typhimurium

Project description:AroA deficient Salmonella Typhimurium – More than an auxotrophic mutant

| PRJNA300406 | ENA

Compensating the fitness costs of synonymous mutations

Project description:Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e. growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, our study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection.

2016-03-11 | PXD003495 | Pride

Systems analysis of Salmonella regulatory mutants

Project description:Sample-matched multi-omic measurements of fourteen virulence-essential regulator mutants were coupled with computational network analysis to efficiently identify Salmonella virulence factors. A subset of computationally predicted virulence factors was determined to be secreted into the host cytoplasm, and two of these, SrfN and PagK2, were required for full mouse virulence and defined a new class of translocated effectors involved in pathogenesis.

2013-10-07 | PXD000390 | Pride

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