Cryptic infection of rats with non-encapsulated variants of Yersinia pestis

Williams, J. E.; Harrison, Daniel N.; Cavanaugh, Dan C.

doi:10.1016/0035-9203(75)90039-5

Cited by 17 publications

(12 citation statements)

References 3 publications

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“…Allegedly resistant host populations typically consist of a mixture of highly susceptible individuals that usually die following infection and more resistant animals that become infected but eventually recover, as indicated by the detection of specific antibodies or resolving Y. pestis lesions in their tissues (49,79,113). Although the evidence is limited, some researchers have proposed that recovered hosts might become chronic carriers of plague, thereby acting as reservoirs for maintaining the disease between transmission seasons or epizootics (113,141,142). Others believe that normally susceptible animals might become infected shortly before entering hibernation, maintain a latent infection while hibernating, and then succumb to plague upon reawakening in the spring (54, 115).…”

Section: Resistance To Plague In Mammalian Host Populationsmentioning

confidence: 96%

NATURAL HISTORY OF PLAGUE: Perspectives from More than a Century of Research

Gage

Kosoy

2005

Annu. Rev. Entomol.

629

669

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For more than a century, scientists have investigated the natural history of plague, a highly fatal disease caused by infection with the gram-negative bacterium Yersinia pestis. Among their most important discoveries were the zoonotic nature of the disease and that plague exists in natural cycles involving transmission between rodent hosts and flea vectors. Other significant findings include those on the evolution of Y. pestis; geographic variation among plague strains; the dynamics and maintenance of transmission cycles; mechanisms by which fleas transmit Y. pestis; resistance and susceptibility among plague hosts; the structure and typology of natural foci; and how landscape features influence the focality, maintenance, and spread of the disease. The knowledge gained from these studies is essential for the development of effective prevention and control strategies.

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Section: Resistance To Plague In Mammalian Host Populationsmentioning

confidence: 96%

NATURAL HISTORY OF PLAGUE: Perspectives from More than a Century of Research

Gage

Kosoy

2005

Annu. Rev. Entomol.

629

669

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“…However, in contrast to the case for lcrV mutations in the 70-kb pCD1 virulence plasmid, Y. pestis carrying mutations in the caf pilus gene cluster of the 100-kb pMT1 plasmid (23,27) (16,19,50). Furthermore, a challenge of F1-immunized mice or rats with Y. pestis strain CO92 resulted in lethal plague disease with fully virulent caf1 mutant variants that were presumably selected by the presence of a specific antibody (13,52). A caf1 mutant strain was also isolated from a plague-infected individual during autopsy (53), suggesting that F1 pili may not be absolutely required for the pathogenesis of human plague.…”

Section: Discussionmentioning

confidence: 99%

LcrV Plague Vaccine with Altered Immunomodulatory Properties

Overheim¹,

DePaolo

DeBord³

et al. 2005

Infect Immun

135

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Yersinia pestis, the causative agent of plague, secretes LcrV (low-calcium-response V or V antigen) during infection. LcrV triggers the release of interleukin 10 (IL-10) by host immune cells and suppresses proinflammatory cytokines such as tumor necrosis factor alpha and gamma interferon as well as innate defense mechanisms required to combat the pathogenesis of plague. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of LcrV as a human vaccine. Here we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271 to 300 (rV10) elicited immune responses that protected mice against a lethal challenge with Y. pestis. Compared to full-length LcrV, rV10 displayed a reduced ability to release IL-10 from mouse and human macrophages. Furthermore, the lipopolysaccharide-stimulated release of proinflammatory cytokines by human or mouse macrophages was inhibited by full-length LcrV but not by the rV10 variant. Thus, it appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.Plague epidemics have likely killed more people worldwide than any other infectious disease (36,54). Mammals, in particular rats, prairie dogs, and gerbils, are the primary reservoir of Yersinia pestis, and human disease transmission occurs by flea bites, aerosol, or contact (15, 17). Flea bite-transmitted Y. pestis infection leads to bubonic plague, with characteristic lymph node swellings and disease symptoms that progress frequently to systemic infection and pneumonia (7,14). Aerosol transmission of virulent Y. pestis, whether during plague epidemics or deliberate dissemination, precipitates pneumonic plague, a rapidly fatal disease with few characteristic symptoms (28). Considering the ubiquitous zoonotic nature of the disease and the possible illegitimate use of Y. pestis as a weapon, there is an urgent need for vaccine development to protect humans against bubonic and pneumonic plague (36).Some, but not all, bubonic plague victims survive the disease, even without therapy, and appear to develop immunity (12,48). Burrows discovered Y. pestis LcrV as a protective antigen which stimulates humoral immune responses in experimental animals that afford protection against plague infection (10, 11). Based on these observations, several laboratories developed recombinant LcrV subunit vaccines, either alone or in combination with other Y. pestis proteins, and demonstrated that a humoral immune response to LcrV confers plague protection in experimental animals (2,21,25,31,32,47). Brubaker and colleagues first showed that LcrV injection of animals stimulates the release of interleukin 10 (IL-10), a cytokine that suppresses innate immune functions (8, 34). LcrV injection also prevents the release of proinflammatory cytokines, such as gamma interferon (IFN-␥) or tumor necrosis factor alpha (TNF-␣), during ...

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“…F1 mutant strains have been isolated previously from mice (8) and from rats that developed fatal plague infections but had received prior immunization with the live attenuated plague vaccine (EV76) (64,65). Previous work revealed an F1-negative strain with a spontaneous 66-bp deletion in the caf promoter that affects expression of the caf operon (18).…”

Section: Discussionmentioning

confidence: 99%

“…An F1 mutant, nonencapsulated plague strain was isolated from autopsy samples from a human plague victim (67), and naturally occurring or genetically engineered F1 variants are thought to cause animal plague infections (7,13,18,(63)(64)(65). Here, we address the possibility that there are different types of breakthrough variants in animals immunized with live attenuated whole-cell vaccines or F1-based subunit vaccines and pursue their molecular analysis.…”

mentioning

confidence: 99%

Yersinia pestisIS1541Transposition Provides for Escape from Plague Immunity

et al. 2009

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Yersinia pestis is perhaps the most feared infectious agent due to its ability to cause epidemic outbreaks of plague disease in animals and humans with high mortality. Plague infections elicit strong humoral immune responses against the capsular antigen (fraction 1 [F1]) of Y. pestis, and F1-specific antibodies provide protective immunity. Here we asked whether Y. pestis generates mutations that enable bacterial escape from protective immunity and isolated a variant with an IS1541 insertion in caf1A encoding the F1 outer membrane usher. The caf1A::IS1541 insertion prevented assembly of F1 pili and provided escape from plague immunity via F1-specific antibodies without a reduction in virulence in mouse models of bubonic or pneumonic plague. F1-specific antibodies interfere with Y. pestis type III transport of effector proteins into host cells, an inhibitory effect that was overcome by the caf1A::IS1541 insertion. These findings suggest a model in which IS1541 insertion into caf1A provides for reversible changes in envelope structure, enabling Y. pestis to escape from adaptive immune responses and plague immunity.

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Cryptic infection of rats with non-encapsulated variants of Yersinia pestis

Cited by 17 publications

References 3 publications

NATURAL HISTORY OF PLAGUE: Perspectives from More than a Century of Research

NATURAL HISTORY OF PLAGUE: Perspectives from More than a Century of Research

LcrV Plague Vaccine with Altered Immunomodulatory Properties

Yersinia pestisIS1541Transposition Provides for Escape from Plague Immunity

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