Plague Toxins — A Critical Review

Rv, Walker

doi:10.1007/978-3-642-46062-3_2

Cited by 9 publications

(5 citation statements)

References 32 publications

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“…The present study complements the findings of earlier workers (7,23,24,25) and firmly establishes the production by P. pestis of a lipopolysaccharide that exhibits classical endotoxic properties and possesses sufficient toxicity to contribute to or account for death in small laboratory animals. The work opens the way for future studies concerning the mechanism of action of P. pestis endotoxin in animals and man, which in turn may lead to the development of improved methods for managing the endotoxemia accompanying plague and other gram-negative bacterial infections.…”

Section: Discussionsupporting

confidence: 89%

Isolation and Biological Characterization of Pasteurella pestis Endotoxin

Albizo¹,

Surgalla²

1970

Infect Immun

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Endotoxin containing 2.1 % nitrogen, 1.6% phosphorus, 22.5 % neutral hexose, 15% hexosamine, 25% esterified and amide-linked fatty acids, and 1.4% protein was isolated from Pasteurella pestis strain Alexander by slight modification of a method adapted by Tauber and Russell. The lipopolysaccharide exhibited classical endotoxic biological properties including: (i) toxicity in mice, guinea pigs, and rabbits; (ii) antigenicity in rabbits; (iii) capacity to evoke a biphasic pyrogenic response in rabbits; (iv) capacity to induce tolerance in mice to the lethal effect of endotoxin; (v) capacity to stimulate rapidly acquired resistance in mice to bacterial infection, and (vi) the capacity to produce the localized and generalized Shwartzman phenomena in rabbits. Findings obtained during the study concerning the occurrence, isolation, toxicity, and other biological properties of P. pestis endotoxin provide new evidence that endotoxin could contribute to death in plague. Early plague investigators proposed that Pasteurella pestis produced an endotoxin that contributed to death in plague (14). Early efforts to isolate the endotoxin by classical methods were unsuccessful (8, 9); however, in more recent attempts the phenol extraction method of Westphal et al. (26) has been used, and considerable success has been achieved (7, 24, 25). It is now known collectively from the studies of Davies (7), Walker et al. (25), Walker (23, 24), and Larrabee et al. (11) that P. pestis produces a lipopolysaccharide that kills mice, guinea pigs, rabbits, and monkeys with symptoms and pathological changes characteristic of endotoxin shock at death. These recent findings lend direct support to the endotoxic death concept in plague proposed by earlier investigators. The present investigation, which involved isolating P. pestis endotoxin and testing the toxic and biological properties of the endotoxin, was undertaken to provide additional knowledge concerning P. pestis endotoxin and to determine whether endotoxin could contribute significantly to the pathogenesis of plague. MATERIALS AND METHODS Stock culture. Fully virulent (guinea pig-passed) P. pestis strain Alexander (LD=o < 20 cells for mice and guinea pigs) possessing fraction I antigen, VW antigens, pigmentation, and pesticinogeny was used as a stock culture. Cultivation of organisms. Blood Agar Base slants (Difco, pH 6.8) were inoculated with stock P. pestis

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Section: Discussionsupporting

confidence: 89%

Isolation and Biological Characterization of Pasteurella pestis Endotoxin

Albizo¹,

Surgalla²

1970

Infect Immun

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“…In our intravenous mouse model, death followed relatively low bacterial loads of less than 108 bacteria per animal, as had been noted previously for experimental plague in mice (37,38,40). We found no evidence of disseminated intravascular coagulation, suggesting that endotoxin is not a major immediate cause of death in our model.…”

Section: Discussionsupporting

confidence: 83%

Differential clearance and host-pathogen interactions of YopE- and YopK- YopL- Yersinia pestis in BALB/c mice

1989

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This study characterized infections in BALB/c mice by the nonpigmented Yersinia pestis KIM and its derivatives lacking the low-Ca2+-response virulence plasmid pCD1 or failing to express selected yersinial outer membrane proteins (YOPs). The parent Y. pestis showed net growth in the spleen by 2 h and in the liver after 7 h; exponential growth in both the liver and spleen culminated in death of the mice starting on day 4, with total bacterial numbers of less than 108 in the blood, liver, and spleen together. The histopathology progressed from microabscesses to extensive coagulative necrosis unaccompanied by further immigration of inflammatory cells. This, together with the relatively low bacterial numbers, suggests a toxigenic mechanism. YopEor YopK-YopLyersiniae were cleared from the spleen but grew in the liver after an initial lag. Their growth was curbed after 1 to 2 days and entered a plateau that lasted 5 to 6 days; viable numbers then declined rapidly. This suggests that these Yopmutations distinguish, at least kinetically, between host responses in liver and spleen. Both strains caused acute inflammation in liver that evolved into structured lesions surrounded by progressively mononuclear inflammation suggestive of a granulomatous response. Accordingly, YOP E and YOPs K and L are necessary in the early days of the infection for net growth in spleen and prolonged growth in the liver; their absence is reflected morphologically by the emergence of cell-mediated immunity in the liver. The YopEand YopK-YopLmutants bound only slightly increased amounts of C3, suggesting that YOPs E, K, and L are protective through mechanisms other than interfering with the binding of complement.

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“…Another unresolved issue is that recombinant Ymt 61 kDa protein produced and purified from E. coli , although it has in vitro PLD activity ( 30 ), did not protect Ymt – Y. pestis when added to an infectious blood meal ( 19 ); and unlike native Ymt purified from Y. pestis by affinity chromatography, is nontoxic to mice ( 31 , 32 ). Original Ymt fractions purified from Y. pestis consisted of two forms of 120 and 240 kDa, and it has been suggested that synergism between Ymt and other Y. pestis factors is responsible for murine toxicity ( 33 , 34 ). The same may be true for the role of Ymt in the flea.…”

Section: Discussionmentioning

confidence: 99%

Role of the Yersinia pestis phospholipase D (Ymt) in the initial aggregation step of biofilm formation in the flea

Jarrett,

Leung,

Motoshi

et al. 2024

mBio

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Transmission of Yersinia pestis by fleas depends on the formation of condensed bacterial aggregates embedded within a gel-like matrix that localizes to the proventricular valve in the flea foregut and interferes with normal blood feeding. This is essentially a bacterial biofilm phenomenon, which at its end stage requires the production of a Y. pestis exopolysaccharide that bridges the bacteria together in a cohesive, dense biofilm that completely blocks the proventriculus. However, bacterial aggregates are evident within an hour after a flea ingests Y. pestis , and the bacterial exopolysaccharide is not required for this process. In this study, we characterized the biochemical composition of the initial aggregates and demonstrated that the yersinia murine toxin (Ymt), a Y. pestis phospholipase D, greatly enhances rapid aggregation following infected mouse blood meals. The matrix of the bacterial aggregates is complex, containing large amounts of protein and lipid (particularly cholesterol) derived from the flea’s blood meal. A similar incidence of proventricular aggregation occurred after fleas ingested whole blood or serum containing Y. pestis , and intact, viable bacteria were not required. The initial aggregation of Y. pestis in the flea gut is likely due to a spontaneous physical process termed depletion aggregation that occurs commonly in environments with high concentrations of polymers or other macromolecules and particles such as bacteria. The initial aggregation sets up subsequent binding aggregation mediated by the bacterially produced exopolysaccharide and mature biofilm that results in proventricular blockage and efficient flea-borne transmission. IMPORTANCE Yersinia pestis , the bacterial agent of plague, is maintained in nature in mammal-flea-mammal transmission cycles. After a flea feeds on a mammal with septicemic plague, the bacteria rapidly coalesce in the flea’s digestive tract to form dense aggregates enveloped in a viscous matrix that often localizes to the foregut. This represents the initial stage of biofilm development that potentiates transmission of Y. pestis when the flea later bites a new host. The rapid aggregation likely occurs via a depletion-aggregation mechanism, a non-canonical first step of bacterial biofilm development. We found that the biofilm matrix is largely composed of host blood proteins and lipids, particularly cholesterol, and that the enzymatic activity of a Y. pestis phospholipase D (Ymt) enhances the initial aggregation. Y. pestis transmitted by flea bite is likely associated with this host-derived matrix, which may initially shield the bacteria from recognition by the host's intradermal innate immune response.

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Plague Toxins — A Critical Review

Cited by 9 publications

References 32 publications

Isolation and Biological Characterization of Pasteurella pestis Endotoxin

Isolation and Biological Characterization of Pasteurella pestis Endotoxin

Differential clearance and host-pathogen interactions of YopE- and YopK- YopL- Yersinia pestis in BALB/c mice

Role of the Yersinia pestis phospholipase D (Ymt) in the initial aggregation step of biofilm formation in the flea

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