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Bacterial cancer therapy using the attenuated fowl-adapted Salmonella enterica serovar Gallinarum.

ABSTRACT: We report here a novel anti-cancer therapy based on an avian-host-specific serotype Salmonella enterica serovar Gallinarum (S. Gallinarum) deficient in ppGpp synthesis. To monitor the tumor targeting, a bioluminescent ΔppGpp S. Gallinarum was constructed and injected intravenously into mice bearing syngeneic and human xenograft tumors. Strong bioluminescent signals were detected specifically in all grafted tumors at 2 days post-injection (dpi). The bacterial counts in normal and tumor tissue at 1 dpi revealed that ΔppGpp S. Gallinarum reached >10⁸ CFU/g in tumor tissue and 10⁶-10⁷ CFU/g in endothelial organs; counts were much lower in other organs. At 16 dpi, ΔppGpp S. Gallinarum counts in tumor tissue decreased to ∼10⁶ CFU/g, while those in the other organs became undetectable. A strong anti-cancer effect was observed after the injection of ΔppGpp S. Gallinarum into BALB/c mice grafted with CT26 colon cancer cells. This could be attributed to reduced virulence, which allowed the administration of at least a 10-fold greater dose (10⁸ CFU) of ΔppGpp S. Gallinarum than other attenuated strains of S. enterica serovar Typhimurium (≤10⁷ CFU). An advantage of the avian-specific S. Gallinarum as a cancer therapeutic should be a reduced capacity to cause infections or harm in humans.

SUBMITTER: Lim D

PROVIDER: S-EPMC10694566 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Bacterial cancer therapy using the attenuated fowl-adapted Salmonella enterica serovar Gallinarum.

Lim Daejin D Kim Kwangsoo K Duysak Taner T So EunA E Jeong Jae-Ho JH Choy Hyon E HE

Molecular therapy oncolytics 20231102

We report here a novel anti-cancer therapy based on an avian-host-specific serotype Salmonella enterica serovar Gallinarum (S. Gallinarum) deficient in ppGpp synthesis. To monitor the tumor targeting, a bioluminescent ΔppGpp S. Gallinarum was constructed and injected intravenously into mice bearing syngeneic and human xenograft tumors. Strong bioluminescent signals were detected specifically in all grafted tumors at 2 days post-injection (dpi). The bacterial counts in normal ...[more]

PMID: 38053546

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Project description:BackgroundThe poultry red mite Dermanyssus gallinae (De Geer, 1778) is a major ectoparasite of poultry. Infestations are found in most laying hen farms in Europe, and breeder flocks have also been reported to be affected. Mite infestation has detrimental effects on animal welfare, it causes significant economic losses, and, additionally, D. gallinae is often considered as a vector for pathogens. Despite suspicion of a close relationship between the poultry red mite and Salmonella enterica enterica serovar Gallinarum biovar Gallinarum (serovar Gallinarum), the causative agent of fowl typhoid disease (FT), there has been no definitive proof of mite-mediated transmission. Therefore, an investigation was conducted to determine if D. gallinae-mediated transmission of serovar Gallinarum could be demonstrated among four different hen groups.MethodsTwo groups of 8 hens (A and B) were experimentally infected with serovar Gallinarum in two isolators. After 7 days, when birds showed signs of FT, about 25,000 mites were introduced. After 3 days, mites were harvested and used to infest two other hen groups of 8 (C and D), in two separate isolators. The health status of hens was constantly monitored; detection and quantification of serovar Gallinarum were performed by PCR and qPCR from mites and organs of dead hens. The maximum likelihood estimation of the infection rate and mite vectorial capacity were calculated.ResultsClinical disease was observed in groups infected with serovar Gallinarum (A and B) and in hens of groups C and D infested with mites harvested from the isolators containing groups A and B. In all four groups, serovar Gallinarum was detected from liver, spleen, ovary, and cecum of hens, thus confirming the diagnosis of FT. Mite analysis demonstrated the presence of the pathogen, with an estimated infection rate ranging between 13.72 and 55.21 infected per thousand mites. Vectorial capacity was estimated to be 73.79.ConclusionsMites harvested from birds infected with serovar Gallinarum were shown to carry the mite, and then to transfer serovar Gallinarum to isolated groups of pathogen-free birds that subsequently showed signs of FT. Mite vectorial capacity was high, demonstrating that D. gallinae should be considered an effective vector of FT.

Project description:Salmonella enterica subspecies enterica serovar Gallinarum biovar Pullorum (S Pullorum) is the etiological agent of pullorum disease, causing white diarrhea with high mortality in chickens. There are many unsolved issues surrounding the epidemiology of S Pullorum, including its origin and transmission history as well as the discordance between its phenotypic heterogeneity and genetic monomorphism. In this paper, we report the results of whole-genome sequencing of a panel of 97 S Pullorum strains isolated between 1962 and 2014 from four countries across three continents. We utilized 6,795 core genome single nucleotide polymorphisms (SNPs) to reconstruct a phylogenetic tree within a spatiotemporal Bayesian framework, estimating that the most recent common ancestor of S Pullorum emerged in ∼914 CE (95% confidence interval [95%CI], 565 to 1273 CE). The extant S Pullorum strains can be divided into four distinct lineages, each of which is significantly associated with geographical distribution. The intercontinental transmissions of lineages III and IV can be traced to the mid-19th century and are probably related to the "Hen Fever" prevalent at that time. Further genomic analysis indicated that the loss or pseudogenization of functional genes involved in metabolism and virulence in S Pullorum has been ongoing since before and after divergence from the ancestor. In contrast, multiple prophages and plasmids have been acquired by S Pullorum, and these have endowed it with new characteristics, especially the multidrug resistance conferred by two large plasmids in lineage I. The results of this study provide insight into the evolution of S Pullorum and prove the efficiency of whole-genome sequencing in epidemiological surveillance of pullorum disease.IMPORTANCE Pullorum disease, an acute poultry septicemia caused by Salmonella Gallinarum biovar Pullorum, is fatal for young chickens and is a heavy burden on poultry industry. The pathogen is rare in most developed countries but still extremely difficult to eliminate in China. Efficient epidemiological surveillance necessitates clarifying the origin of the isolates from different regions and their phylogenic relationships. Genomic epidemiological analysis of 97 S Pullorum strains was carried out to reconstruct the phylogeny and transmission history of S Pullorum. Further analysis demonstrated that functional gene loss and acquisition occurred simultaneously throughout the evolution of S Pullorum, both of which reflected adaptation to the changing environment. The result of our study will be helpful in surveillance and prevention of pullorum disease.

Project description:Salmonella enterica serovar Gallinarum biovars Gallinarum and Pullorum cause severe chicken salmonellosis, a disease associated with high mortality and morbidity among chickens worldwide. The conventional serotyping and biochemical reactions have been used to identify Salmonella serovars. However, the conventional methods are complicated, time-consuming, laborious, and expensive. Furthermore, it is challenging to distinguish S. Gallinarum and S. Pullorum via biochemical assays and serotyping because of their antigenic similarity. Although various PCR methods were established, a PCR protocol to detect and discriminate S. Gallinarum and S. Pullorum simultaneously is lacking. Herein, a one-step multiplex PCR method was established for the accurate identification and discrimination of S. Pullorum and S. Gallinarum. Three specific genes were used for the multiplex PCR method, with the I137_14445 and ybgL genes being the key targets to identify and differentiate S. Gallinarum and S. Pullorum, and stn being included as a reference gene for the Salmonella genus. In silico analysis showed that the I137_14445 gene is present in all Salmonella serovars, except for S. Gallinarum, and could therefore be used for the identification of S. Gallinarum. A 68-bp sequence deficiency in ybgL was found only in S. Pullorum compared to other Salmonella serovars, and this could therefore be used for the specific identification of S. Pullorum. The developed PCR assay was able to distinguish S. Gallinarum and S. Pullorum among 75 various Salmonella strains and 43 various non-Salmonella pathogens with excellent specificity. The detection limit for the genomic DNA of S. Gallinarum and S. Pullorum was 21.4 pg./μL, and the detectable limit for bacterial cells was 100 CFU. The developed PCR method was used for the analysis of Salmonella isolates in a chicken farm. This PCR system successfully discriminated S. Gallinarum and S. Pullorum from other different Salmonella serovars. The PCR results were confirmed by the conventional serotyping method. The newly established multiplex PCR is a simple, accurate, and cost-effective method for the timely identification and differentiation of S. Pullorum and S. Gallinarum.

Dataset Information

Bacterial cancer therapy using the attenuated fowl-adapted Salmonella enterica serovar Gallinarum.

Publications

Bacterial cancer therapy using the attenuated fowl-adapted <i>Salmonella enterica</i> serovar Gallinarum.

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