Lathem, W. W., Crosby, S. D., Miller, V. L. & Goldman, W. E. Progression of primary pneumonic plague: a mouse model of infection, pathology, and bacterial transcriptional activity. Proc. Natl Acad. Sci. USA 102, 17786-17791

Department of Molecular Microbiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2006; 102(49):17786-91. DOI: 10.1073/pnas.0506840102
Source: PubMed


Although pneumonic plague is the deadliest manifestation of disease caused by the bacterium Yersinia pestis, there is surprisingly little information on the cellular and molecular mechanisms responsible for Y. pestis-triggered pathology in the lung. Therefore, to understand the progression of this unique disease, we characterized an intranasal mouse model of primary pneumonic plague. Mice succumbed to a purulent multifocal severe exudative bronchopneumonia that closely resembles the disease observed in humans. Analyses revealed a strikingly biphasic syndrome, in which the infection begins with an antiinflammatory state in the first 24-36 h that rapidly progresses to a highly proinflammatory state by 48 h and death by 3 days. To assess the adaptation of Y. pestis to a mammalian environment, we used DNA microarray technology to analyze the transcriptional responses of the bacteria during interaction with the mouse lung. Included among the genes up-regulated in vivo are those comprising the yop-ysc type III secretion system and genes contained within the chromosomal pigmentation locus, validating the use of this technology to identify loci essential to the virulence of Y. pestis.

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Available from: Wyndham W Lathem, Mar 17, 2014
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    • "Pulmonary models of enteric infection (Fisher et al., 2007; Lathem et al., 2005; Logsdon & Mecsas, 2006). Of the pathogens reviewed here, Yersinae, is the only genus for which both pneumonic and enteric modes of infection exist. "
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    ABSTRACT: Many pathogens are capable of causing a fulminant infection in pulmonary tissues of mammals. Animal models have provided an extensive understanding of the genetic and molecular mechanisms of bacterial pathogenesis as well as host immune response in the lungs. Many clinically relevant Gram-negative bacteria are host-restricted. Thus, the powerful, informative tools of mouse models are not available for study with these organisms. However, over the past 30 years, enterprising work has demonstrated the utility of pulmonary infection with enteric pathogens. Such infection models have increased our understanding host-pathogen interactions in these organisms. Here, we provide a review and comparison of lung models of infection with enteric, Gram-negative bacteria relative to naturally occurring lung pathogens.
    Full-text · Article · Oct 2013 · Pathogens and Disease
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    • "A lung infection model using the Yptb serotype III strain IP2666 pIB1NdeI (IP2666NdeI) has been previously established (Fisher et al., 2007). In this model, IP2666NdeI robustly colonized the lungs, but only sporadically colonized the spleen and liver when compared with Y. pestis (Lathem et al., 2005; Agar et al., 2009; Price et al., 2012). Serotype Ib strains of Yptb are more closely related to Y. pestis than serotype III strains (Achtman et al., 1999; Skurnik et al., 2000), and therefore we hypothesized that the serotype Ib IP32953 strain would be a more virulent lung pathogen than IP2666NdeI. "
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    ABSTRACT: A Yersinia pseudotuberculosis (Yptb) murine model of lung infection was previously developed using the serotype III IP2666NdeI strain, which robustly colonized lungs but only sporadically disseminated to the spleen and liver. We demonstrate here that a serotype Ib Yptb strain, IP32953, colonizes the lungs at higher levels and disseminates more efficiently to the spleen and liver compared to IP2666NdeI . The role of adhesins was investigated during IP32953 lung infection by constructing isogenic Δail, Δinv, ΔpsaE and ΔyadA mutants. An IP32953ΔailΔyadA mutant initially colonized but failed to persist in the lungs and failed to disseminate to the spleen and liver. Yptb expressing these adhesins selectively bound to and targeted neutrophils for translocation of Yops. This selective targeting was critical for virulence because persistence of the ΔailΔyadA mutant was restored following intranasal infection of neutropenic mice. Furthermore, Ail and YadA prevented killing by complement-mediated mechanisms during dissemination to and/or growth in the spleen and liver, but not in the lungs. Combined, these results demonstrate that Ail and YadA are critical, redundant virulence factors during lung infection, because they thwart neutrophils by directing Yop-translocation specifically into these cells.
    Full-text · Article · Oct 2013 · Cellular Microbiology
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    • "The intranasal mouse model of primary pneumonic plague was developed as previously described [44,45]. Y. pestis strain 201 was grown to mid-exponential phase in BHI medium aforementioned. "
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    ABSTRACT: Small non-coding RNAs (sRNAs) facilitate host-microbe interactions. They have a central function in the post-transcriptional regulation during pathogenic lifestyles. Hfq, an RNA-binding protein that many sRNAs act in conjunction with, is required for Y. pestis pathogenesis. However, information on how Yersinia pestis modulates the expression of sRNAs during infection is largely unknown. We used RNA-seq technology to identify the sRNA candidates expressed from Y. pestis grown in vitro and in the infected lungs of mice. A total of 104 sRNAs were found, including 26 previously annotated sRNAs, by searching against the Rfam database with 78 novel sRNA candidates. Approximately 89% (93/104) of these sRNAs from Y. pestis are shared with its ancestor Y. pseudotuberculosis. Ninety-seven percent of these sRNAs (101/104) are shared among more than 80 sequenced genomes of 135 Y. pestis strains. These 78 novel sRNAs include 62 intergenic and 16 antisense sRNAs. Fourteen sRNAs were selected for verification by independent Northern blot analysis. Results showed that nine selected sRNA transcripts were Hfq-dependent. Interestingly, three novel sRNAs were identified as new members of the transcription factor CRP regulon. Semi-quantitative analysis revealed that Y. pestis from the infected lungs induced the expressions of six sRNAs including RyhB1, RyhB2, CyaR/RyeE, 6S RNA, RybB and sR039 and repressed the expressions of four sRNAs, including CsrB, CsrC, 4.5S RNA and sR027. This study is the first attempt to subject RNA from Y. pestis-infected samples to direct high-throughput sequencing. Many novel sRNAs were identified and the expression patterns of relevant sRNAs in Y. pestis during in vitro growth and in vivo infection were revealed. The annotated sRNAs accounted for the most abundant sRNAs either expressed in bacteria grown in vitro or differentially expressed in the infected lungs. These findings suggested these sRNAs may have important functions in Y. pestis physiology or pathogenesis.
    Full-text · Article · Sep 2013 · PLoS ONE
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