Biosafety Level 2 Model of Pneumonic Plague and Protection Studies with F1 and Psa

Galván, Estela M.; Nair, Manoj Kumar Mohan; Chen, Huaiqing; Piero, Fábio Del; Schifferli, Dieter M.

doi:10.1128/iai.00382-10

Cited by 22 publications

(28 citation statements)

References 72 publications

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“…A mouse BSL2 model of pneumonic plague (Galván et al 2010) was used to compare the virulence of wild-type and Δ ompA Y. pestis strains. C57BL/6 mice were inoculated intranasally with equal numbers of Y. pestis KIM5 (Pgm-) and an isogenic ompA deletion strain.…”

Section: Resultsmentioning

confidence: 99%

The outer membrane protein A (OmpA) of Yersinia pestis promotes intracellular survival and virulence in mice

Bartra

Gong

Lorica

et al. 2012

Microbial Pathogenesis

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The plague bacterium Yersinia pestis has a number of well-described strategies to protect itself from both host cells and soluble factors. In an effort to identify additional anti-host factors, we employed a transposon site hybridization (TraSH)-based approach to screen 105 Y. pestis mutants in an in vitro infection system. In addition to loci encoding various components of the well-characterized type III secretion system (T3SS), our screen unambiguously identified ompA as a pro-survival gene. We go on to show that an engineered Y. pestis ΔompA strain, as well as a ΔompA strain of the closely related pathogen Y. pseudotuberculosis, have fully functioning T3SSs but are specifically defective in surviving within macrophages. Additionally, the Y. pestis ΔompA strain was outcompeted by the wild-type strain in a mouse co-infection assay. Unlike in other bacterial pathogens in which OmpA can promote adherence, invasion, or serum resistance, the OmpA of Y. pestis is restricted to enhancing intracellular survival. Our data show that OmpA of the pathogenic Yersinia is a virulence factor on par with the T3SS.

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Section: Resultsmentioning

confidence: 99%

The outer membrane protein A (OmpA) of Yersinia pestis promotes intracellular survival and virulence in mice

Bartra

Gong

Lorica

et al. 2012

Microbial Pathogenesis

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“…There is a need for a greater understanding of the disease process, as well as the development of new vaccine and molecular therapy candidates, and a greater understanding of the roles and functions of these candidates in Y. pestis pathogenesis. One such candidate is the chaperone/usher fimbria Psa, which recently was shown to provide incomplete but significant protection against an attenuated Y. pestis strain (20). The operon encoding this fimbria is expressed at the flea vector temperature of 26°C, but a large increase in expression is observed in the mammalian host and in vitro under mammalian host-like conditions such as a temperature shift and a low pH (24,30).…”

Section: Discussionmentioning

confidence: 99%

“…The data represent three independent experiments. The numbers of tissue samples harvested for the wild-type and ⌬psaA, ⌬caf1, and ⌬psaA ⌬caf1 mutant strains, respectively, were 20,7,14 organisms of the wild-type and ⌬psaA mutant strains, and doses ranging between 100 and 10 5 organisms of the ⌬caf1 and ⌬psaA ⌬caf1 mutant strains. The LD 50 of the wild-type strain in C57BL/6J infected by the s.c. route was determined to be ϳ1 CFU, which is consistent with previous reports ( Fig.…”

Section: Both Psaa and Caf1 Are Required For Bubonic Infectionmentioning

confidence: 99%

The Dependence of the Yersinia pestis Capsule on Pathogenesis Is Influenced by the Mouse Background

et al. 2011

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Yersinia pestis is a highly pathogenic Gram-negative organism and the causative agent of bubonic and pneumonic plague. Y. pestis is capable of causing major epidemics; thus, there is a need for vaccine targets and a greater understanding of the role of these targets in pathogenesis. Two prime Y. pestis vaccine candidates are the usher-chaperone fimbriae Psa and Caf. Herein we report that Y. pestis requires, in a nonredundant manner, both PsaA and Caf1 to achieve its full pathogenic ability in both pneumonic and bubonic plague in C57BL/6J mice. Deletion of psaA leads to a decrease in the organ bacterial burden and to a significant increase in the 50% lethal dose (LD 50 ) after subcutaneous infection. Deletion of caf1 also leads to a significant decrease in the organ bacterial burden but more importantly leads to a significantly greater increase in the LD 50 than was observed for the ⌬psaA mutant strain after subcutaneous infection of C57BL/6J mice. Furthermore, the degree of attenuation of the ⌬caf1 mutant strain is mouse background dependent, as the ⌬caf1 mutant strain was attenuated to a lesser degree in BALB/cJ mice by the subcutaneous route than in C57BL/6J mice. This observation that the degree of requirement for Caf1 is dependent on the mouse background indicates that the virulence of Y. pestis is dependent on the genetic makeup of its host and provides further support for the hypothesis that PsaA and Caf1 have different targets.

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“…Psa has been shown to agglutinate red blood cells (9) and, like F1, to inhibit phagocytosis by macrophages (10). A number of studies have also highlighted that Psa is expressed in vivo in infected tissues (11) and plays a key role in virulence of Y. pestis (12,13). Recent studies have shown that the Psa antigen induces a robust immune response and induces significant albeit incomplete protection in a murine model of pneumonic plague (11).…”

mentioning

confidence: 99%

“…A number of studies have also highlighted that Psa is expressed in vivo in infected tissues (11) and plays a key role in virulence of Y. pestis (12,13). Recent studies have shown that the Psa antigen induces a robust immune response and induces significant albeit incomplete protection in a murine model of pneumonic plague (11). Psa has also been shown to mediate binding to cells, including human respiratory tract epithelial cells (7,9), as well as to pulmonary surfactant (5), which coats the alveolar surface of lungs.…”

mentioning

confidence: 99%

Structural basis for the specific recognition of dual receptors by the homopolymeric pH 6 antigen (Psa) fimbriae of Yersinia pestis

Bao

Nair

Tang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The pH 6 antigen (Psa) of Yersinia pestis consists of fimbriae that bind to two receptors: β1-linked galactosyl residues in glycosphingolipids and the phosphocholine group in phospholipids. Despite the ubiquitous presence of either moiety on the surface of many mammalian cells, Y. pestis appears to prefer interacting with certain types of human cells, such as macrophages and alveolar epithelial cells of the lung. The molecular mechanism of this apparent selectivity is not clear. Site-directed mutagenesis of the consensus choline-binding motif in the sequence of PsaA, the subunit of the Psa fimbrial homopolymer, identified residues that abolish galactosylceramide binding, phosphatidylcholine binding, or both. The crystal structure of PsaA in complex with both galactose and phosphocholine reveals separate receptor binding sites that share a common structural motif, thus suggesting a potential interaction between the two sites. Mutagenesis of this shared structural motif identified Tyr126, which is part of the choline-binding consensus sequence but is found in direct contact with the galactose in the structure of PsaA, important for both receptor binding. Thus, this structure depicts a fimbrial subunit that forms a polymeric adhesin with a unique arrangement of dual receptor binding sites. These findings move the field forward by providing insights into unique types of multiple receptor-ligand interactions and should steer research into the synthesis of dual receptor inhibitor molecules to slow down the rapid progression of plague.adhesin-receptor complex | adhesion | ligand binding | sugar binding | phosphocholine binding

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Biosafety Level 2 Model of Pneumonic Plague and Protection Studies with F1 and Psa

Cited by 22 publications

References 72 publications

The outer membrane protein A (OmpA) of Yersinia pestis promotes intracellular survival and virulence in mice

The outer membrane protein A (OmpA) of Yersinia pestis promotes intracellular survival and virulence in mice

The Dependence of the Yersinia pestis Capsule on Pathogenesis Is Influenced by the Mouse Background

Structural basis for the specific recognition of dual receptors by the homopolymeric pH 6 antigen (Psa) fimbriae of Yersinia pestis

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