<i>Yersinia pseudotuberculosis</i> disseminates directly from a replicating bacterial pool in the intestine

Barnes, Penelope D.; Bergman, Molly A.; Mecsas, Joan; Isberg, Ralph R.

doi:10.1084/jem.20060905

Cited by 140 publications

(151 citation statements)

References 46 publications

(57 reference statements)

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“…5). Similar bottlenecks have been described for enteric pathogens (27)(28)(29) after an oral route of inoculation, and it will be interesting to determine the precise nature of this bottleneck in the future. To bypass the bottleneck, we performed the screen after i.p.…”

Section: Discussionmentioning

confidence: 93%

In vivo negative selection screen identifies genes required for Francisella virulence

Weiss

Brotcke²,

Henry³

et al. 2007

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

298

432

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Francisella tularensis subverts the immune system to rapidly grow within mammalian hosts, often causing tularemia, a fatal disease. This pathogen targets the cytosol of macrophages where it replicates by using the genes encoded in the Francisella pathogenicity island. However, the bacteria are recognized in the cytosol by the host's ASC/caspase-1 pathway, which is essential for host defense, and leads to macrophage cell death and proinflammatory cytokine production. We used a microarray-based negative selection screen to identify Francisella genes that contribute to growth and/or survival in mice. The screen identified many known virulence factors including all of the Francisella pathogenicity island genes, LPS O-antigen synthetic genes, and capsule synthetic genes. We also identified 44 previously unidentified genes that were required for Francisella virulence in vivo, indicating that this pathogen may use uncharacterized mechanisms to cause disease. Among these, we discovered a class of Francisella virulence genes that are essential for growth and survival in vivo but do not play a role in intracellular replication within macrophages. Instead, these genes modulate the host ASC/caspase-1 pathway, a previously unidentified mechanism of Francisella pathogenesis. This finding indicates that the elucidation of the molecular mechanisms used by other uncharacterized genes identified in our screen will increase our understanding of the ways in which bacterial pathogens subvert the immune system. macrophage ͉ pathogenesis ͉ ASC ͉ caspase-1

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Section: Discussionmentioning

confidence: 93%

In vivo negative selection screen identifies genes required for Francisella virulence

Weiss

Brotcke²,

Henry³

et al. 2007

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

298

432

View full text Add to dashboard Cite

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“…Yersinia pseudotuberculosis is an enteropathogen that causes gastrointestinal disorders, usually self-limiting enteritis and mesenteric lymphadenitis [1]. In the mouse oral infection model, enteropathogenic yersiniae produce systemic disease, the bacteria replicating in the small intestine, invading the Peyer's patches and disseminating to the liver and spleen [2,3].…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to Yersinia pseudotuberculosis Infection is Linked to the Pattern of Macrophage Activation

Tansini

Medeiros

2009

Scand J Immunol

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T helper 1 cells play a crucial role in the clearance of Yersinia pseudotuberculosis infection. By producing cytokines and presenting antigens to T cells, activated macrophages can orientate the adaptive immune response. The pathway used by macrophages to metabolize arginine has been employed as an important parameter to discriminate their activation state. In this study, the pattern of macrophage activation in Y. pseudotuberculosis-infected BALB ⁄ c (Yersinia-susceptible) and C57BL ⁄ 6 (Yersinia-resistant) mice and their immunostimulatory capacity were analysed. In the early phase of infection, macrophages obtained from C57BL ⁄ 6 mice produced higher levels of NO, lower arginase activity, and larger amounts of IL-12 and TNF-a than macrophages from BALB ⁄ c mice. On the other hand, macrophages derived from BALB ⁄ c mice produced higher levels of IL-10 and TGF-b than C57BL ⁄ 6 mice. The Y. pseudotuberculosis infection leads to a fall in the macrophage immunostimulatory capacity of both strains of mice, with T-cell proliferation significantly reduced 12 h after infection. Moreover, we observed in the supernatant of co-culture of macrophages from infected mice with T lymphocytes from heat-killed Yersiniaimmunized mice lower IFN-c production by cells from BALB ⁄ c mice than by C57BL ⁄ 6 mice, and IL-4 was produced only by BALB ⁄ c mice on the first-and third-day post-infection. These results suggest that the pattern of macrophage activation is associated with susceptibility and resistance to Y. pseudotuberculosis infection in BALB ⁄ c and C57BL ⁄ 6 mice.

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“…Though tempting to consider, bacterial infections do not necessarily take advantage of one site and disseminate unidirectionally from that portal of entry [149][150][151]282]. Pathogens can disseminate through multiple routes, leading to several smaller populations colonizing unique areas of the host or a small population arising from an initial site that goes on to disseminate throughout the host [150,282].…”

Section: Clonal Analysis As a Tool To Understand Population Dynamics mentioning

confidence: 99%

“…However, very little is known about the evolutionary implications that occur when infecting the host. Several bacterial pathogens are known to undergo a population bottleneck during infection [149][150][151]. Population bottlenecks occur when there is a non-selective decrease in an organism's population that leads to a decrease in the genetic diversity of a population.…”

Section: Evolution and Global Phylogenetic Analysis Of Strainsmentioning

confidence: 99%

“…Such an approach allows for analysis of the changes in population structure, migration, and replication that occurred within the host during the infection ( Figure 4B). These analyses have been used to determine the sequence of dissemination as well as identify population bottlenecks for several pathogens [149][150][151]287]. A bottleneck within an infected host occurs when there is a non-selective decrease in the proportion of bacteria relative to a previous infected site.…”

Section: Introductionmentioning

confidence: 99%

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Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

Lowe

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Bacillus anthracis is a Gram positive sporulating bacterium that is the causative agent of anthrax. Early steps in dissemination are understudied due to the asymptomatic and asynchronous nature of B. anthracis infections. The goals of these studies are to establish a model of the early steps of B. anthracis infections and examine how the initial site of infection and exotoxin production affect bacterial dissemination. In these studies, a mouse model was used in combination with a bioluminescent signature tagged library to determine how B.anthracis disseminates through the host and the roles of an exotoxin component, lethal factor, in colonization and dissemination. This library allowed for real time observation of dissemination and analysis of bacterial population dynamics. In the first set of experiments, mice were infected via inhalational or subcutaneous routes with the tagged library to determine how the bacterial population changed during dissemination. In inhalational and subcutaneous infections, the disseminated population was comprised of a small subset of the original library.This indicated the presence of a population bottleneck, a random decrease in genetic diversity during the infection. Surprisingly, the diminishment and location of the bottleneck varied depending on the initial site of infection. This suggested B. anthracis exploits multiple host environments and some sites may be more permissive for dissemination than others. In the second set of experiments, mice were infected with a signature tagged library where a portion of clones lacked lethal factor. Lethal factor is known to be an important virulence factor as deletion results in attenuated or complete loss of virulence in most animal models. Host survival increased when < 10% of the library produced lethal factor, but few other differences were observed. Furthermore, decreases in the proportion of lethal factor producing clones led to fewer clones disseminating. These findings suggest that a threshold of lethal factor must be ii produced for colonization and dissemination to occur in vivo. In total, this work provides an understanding of how B. anthracis is able to rapidly disseminate from a several tissues and gives insights in where future therapeutics should be focused to reduce disease incidence.iii

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Yersinia pseudotuberculosis disseminates directly from a replicating bacterial pool in the intestine

Cited by 140 publications

References 46 publications

In vivo negative selection screen identifies genes required for Francisella virulence

In vivo negative selection screen identifies genes required for Francisella virulence

Susceptibility to Yersinia pseudotuberculosis Infection is Linked to the Pattern of Macrophage Activation

Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

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