The effect of adding iron to mucin on the enhancement of virulence for mice of Salmonella typhi strain TY 2

Powell, Calvin J.; DeSett, Clayton R.; Lowenthal, Joseph P.; Berman, Sanford

doi:10.1016/s0092-1157(80)80049-7

Cited by 25 publications

(16 citation statements)

References 9 publications

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“…Mice were challenged on day 56 with 3.3×10 5 cfu per mouse of wild-type ATCC 9150 S. Paratyphi A, freshly prepared as described above for the LD 50 studies. Iron (8 µl of 5% ammonium iron (III) citrate to 1 ml of mucin) was added to the bacterial suspension to increase virulence [27]. Following the challenge, mice were monitored every 6 h for 72 h for mortality or any signs of significant morbidity.…”

Section: Methodsmentioning

confidence: 99%

Cell-Associated Flagella Enhance the Protection Conferred by Mucosally-Administered Attenuated Salmonella Paratyphi A Vaccines

et al. 2011

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BackgroundAntibiotic-resistant Salmonella enterica serovar Paratyphi A, the agent of paratyphoid A fever, poses an emerging public health dilemma in endemic areas of Asia and among travelers, as there is no licensed vaccine. Integral to our efforts to develop a S. Paratyphi A vaccine, we addressed the role of flagella as a potential protective antigen by comparing cell-associated flagella with exported flagellin subunits expressed by attenuated strains.Methodology S. Paratyphi A strain ATCC 9150 was first deleted for the chromosomal guaBA locus, creating CVD 1901. Further chromosomal deletions in fliD (CVD 1901D) or flgK (CVD 1901K) were then engineered, resulting in the export of unpolymerized FliC, without impairing its overall expression. The virulence of the resulting isogenic strains was examined using a novel mouse LD50 model to accommodate the human-host restricted S. Paratyphi A. The immunogenicity of the attenuated strains was then tested using a mouse intranasal model, followed by intraperitoneal challenge with wildtype ATCC 9150.ResultsMucosal (intranasal) immunization of mice with strain CVD 1901 expressing cell-associated flagella conferred superior protection (vaccine efficacy [VE], 90%) against a lethal intraperitoneal challenge, compared with the flagellin monomer-exporting mutants CVD 1901K (30% VE) or CVD 1901D (47% VE). The superior protection induced by CVD 1901 with its cell-attached flagella was associated with an increased IgG2a∶IgG1 ratio of FliC-specific antibodies with enhanced opsonophagocytic capacity.ConclusionsOur results clearly suggest that enhanced anti-FliC antibody-mediated clearance of S. Paratyphi A by phagocytic cells, induced by vaccines expressing cell-associated rather than exported FliC, might be contributing to the vaccine-induced protection from S. Paratyphi A challenge in vivo. We speculate that an excess of IgG1 anti-FliC antibodies induced by the exported FliC may compete with the IgG2a subtype and block binding to specific phagocyte Fc receptors that are critical for clearing an S. Paratyphi A infection.

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Section: Methodsmentioning

confidence: 99%

Cell-Associated Flagella Enhance the Protection Conferred by Mucosally-Administered Attenuated Salmonella Paratyphi A Vaccines

et al. 2011

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“…The number of apoptotic cells was determined by using an in situ cell death detection kit with fluorescein (Boehringer Mannheim GmbH) according to the manufacturer's instructions. The mouse mucin model described by Powell et al (44) was used for determination of the 50% lethal dose (LD 50 ) (45).…”

Section: Methodsmentioning

confidence: 99%

Characterization of a Novel Intracellularly Activated Gene from Salmonella enterica Serovar Typhi

et al. 2002

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A Salmonella enterica serovar Typhi gene that is selectively up-regulated upon bacterial invasion of eukaryotic cells was characterized. The open reading frame encodes a 298-amino-acid hydrophobic polypeptide (30.8 kDa), which is predicted to be an integral membrane protein with nine membrane-spanning domains. The protein is closely related (87 to 94% reliability) to different transport and permease systems. Gene expression under laboratory conditions was relatively weak; however, sevenfold induction was observed in a high-osmolarity medium (300 mM NaCl). The growth pattern in a laboratory medium of a serovar Typhi strain Ty2 derivative containing a 735-bp in-frame deletion in this gene, named gaiA (for gene activated intracellularly), was not affected. In contrast, the mutant was partially impaired in intracellular survival in murine peritoneal macrophages, as well as in human monocyte-derived macrophages. However, in the case of human macrophages, this survival defect was modest and evident only at late infection times (24 h). Despite the distinct intracellular survival kinetics displayed in macrophages of different species, the gaiA null mutant was significantly affected in its potential to trigger apoptosis in both murine and human macrophages. Provision of the gaiA gene in trans resulted in complementation of these phenotypes. Interestingly, the absence of a functional gaiA gene caused a marked attenuation in the mouse mucin model, as shown by the increase (3 orders of magnitude) in the 50% lethal dose of the mutant strain over that of the parental strain Ty2 (P < 0.05). Altogether, these data indicate that the product encoded by the gaiA gene is required for triggering apoptosis and bacterial survival within murine macrophages, which is consistent with the in vivo results obtained in the mouse mucin model. However, gaiA was not required for initial intracellular survival in human cells, indicating that its role in the natural host might be more complex than is suggested by the studies performed in the murine system.

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“…Salmonella Typhi and Salmonella Paratyphi A are human host restricted and are normally asymptomatic in mice. However, a lethal infection can be produced in mice by suspending the bacteria in 5 to 10% (wt/vol) hog gastric mucin and then injecting the suspension intraperitoneally (43)(44)(45)(46). In immunization studies, dosing mice with live attenuated Salmonella Typhi vaccines was ineffective by the orogastric route but highly immunogenic when vaccines were given intranasally (47).…”

Section: Systemic Infection Small Animal Modelsmentioning

confidence: 99%

Animal Models for Salmonellosis: Applications in Vaccine Research

Higginson

Simon

Tennant

2016

Clin Vaccine Immunol

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Salmonellosis remains an important cause of human disease worldwide. While there are several licensed vaccines for Salmonella enterica serovar Typhi, these vaccines are generally ineffective against other Salmonella serovars. Vaccines that target paratyphoid and nontyphoidal Salmonella serovars are very much in need. Preclinical evaluation of candidate vaccines is highly dependent on the availability of appropriate scientific tools, particularly animal models. Many different animal models exist for various Salmonella serovars, from whole-animal models to smaller models, such as those recently established in insects. Here, we discuss various mouse, rat, rabbit, calf, primate, and insect models for Salmonella infection, all of which have their place in research. However, choosing the right model is imperative in selecting the best vaccine candidates for further clinical testing. In this minireview, we summarize the various animal models that are used to assess salmonellosis, highlight some of the advantages and disadvantages of each, and discuss their value in vaccine development.A nimal models are indispensable tools for assessing candidate vaccines, with preclinical animal safety, immunogenicity, and efficacy data being prerequisite for regulatory agencies such as the U.S. Food and Drug Administration (FDA) prior to undertaking early-stage clinical trials. However, not all animal models are created equal. While some models are highly robust and closely mimic clinical infection, others are contrived and far removed from clinical relevance. Choosing the right animal model for the vaccine under investigation is imperative in determining its safety and/or effectiveness.Salmonella spp. are often used as model organisms to study bacterial pathogenesis and host-microbe interactions, due to the ability of certain Salmonella serovars to readily infect animals. As such, there are a myriad of animal models available to vaccine developers. These range from colonization or lethality models to those involving complex surgical techniques (Table 1). The choice of model is often related not only to relevance but also cost, ethics, housing requirements, and the availability of appropriate technical expertise. While most researchers utilize one model or another, integration of data from multiple animal models can provide a more complete understanding of the safety of a candidate vaccine and/or predict how a potential vaccine may perform in humans. In this minireview, we provide background on Salmonella clinical syndromes and pathogenesis and then summarize the various animal models that have been used for Salmonella vaccine research. We include a brief discussion of the technical aspects, advantages, and limitations of each model, followed by a review of the literature surrounding its use in vaccine evaluation. While there has been considerable development for veterinary Salmonella vaccines, here we will focus solely on vaccines and models for human salmonellosis.

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The effect of adding iron to mucin on the enhancement of virulence for mice of Salmonella typhi strain TY 2

Cited by 25 publications

References 9 publications

Cell-Associated Flagella Enhance the Protection Conferred by Mucosally-Administered Attenuated Salmonella Paratyphi A Vaccines

Cell-Associated Flagella Enhance the Protection Conferred by Mucosally-Administered Attenuated Salmonella Paratyphi A Vaccines

Characterization of a Novel Intracellularly Activated Gene from Salmonella enterica Serovar Typhi

Animal Models for Salmonellosis: Applications in Vaccine Research

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