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A comprehensive analysis of blood host responses to Yersinia Pestis infection Temporal Progression of Pneumonic Plague in Blood of Nonhuman Primate: A Transcriptomic Analysis

ABSTRACT: transcriptomic analyses showed there was a very rapid proliferation of Y. pestis in assault on African green monkeys. The bacterial loads were enumerated in the blood at delayed time points supporting earlier observations (Layton et al., 2011). Interpretation of transcriptomic changes reveals that the host defense has been essentially shattered, and the process of multi-organ failure was initiated one day after inhalation exposure. At 24 h post-exposure, the diseased animals were possibly at the middle of their survival curves. Hence, such molecular indicators could have critical therapeutic values, particularly when therapies fail to intervene at the earliest opportunity. In the early phase of pathogenesis, systematic reprogramming of both adaptive and innate immunity programs is mediated, leading to sepsis. Results suggest the possibility of early molecular perturbations in the lungs and muscle tissues, and catabolic related activities, such as biosynthesis. Apoptosis ensued at the early stage, which potentially became rapid by recruiting an increasing number of apoptotic networks. Beyond 24 h, rapid apoptosis could have acted in concert with hypercytokinemia and hyperchemokinemia, resulting in failures of many peripheral organs.

ORGANISM(S): Chlorocebus aethiops Macaca mulatta

PROVIDER: GSE63560 | GEO | 2016/01/14

SECONDARY ACCESSION(S): PRJNA268214

REPOSITORIES: GEO

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Project description:transcriptomic analyses showed there was a very rapid proliferation of Y. pestis in assault on African green monkeys. The bacterial loads were enumerated in the blood at delayed time points supporting earlier observations (Layton et al., 2011). Interpretation of transcriptomic changes reveals that the host defense has been essentially shattered, and the process of multi-organ failure was initiated one day after inhalation exposure. At 24 h post-exposure, the diseased animals were possibly at the middle of their survival curves. Hence, such molecular indicators could have critical therapeutic values, particularly when therapies fail to intervene at the earliest opportunity. In the early phase of pathogenesis, systematic reprogramming of both adaptive and innate immunity programs is mediated, leading to sepsis. Results suggest the possibility of early molecular perturbations in the lungs and muscle tissues, and catabolic related activities, such as biosynthesis. Apoptosis ensued at the early stage, which potentially became rapid by recruiting an increasing number of apoptotic networks. Beyond 24 h, rapid apoptosis could have acted in concert with hypercytokinemia and hyperchemokinemia, resulting in failures of many peripheral organs. Following a published report (Layton et al., 2011), the present study was designed to expose the nonhuman primates with a target dose of 100 Â± 50 ED50 aerosolized Y. pestis strain CO92 under ABSL-3 conditions. Seventy-two hours prior to aerosol exposure, all animals were moved into the ABSL-3 for acclimatization. As described in Figure S1, initial blood draws were carried out 24 h before Y. pestis aerosol challenge. The animals were challenged via aerosol with 1 x 106 virulent organisms while under anesthesia with 4 mg/kg Telazol (Fort Dodge Animal Health, Fort Dodge, IA). Post-exposure clinical illness and disseminated infection were evaluated by direct clinical observations. All animals within each group were exposed on the same day at 30 minute intervals, and subsequent blood draws were conducted at 45 m, 6 h, 9 h, 12 h, 18 h, 24 h, 32 h and 42 h.

Project description:Bacterial pathogenesis depends on changes in metabolic and virulence gene expression in response to changes within a pathogen's environment. The plague-causing pathogen, Yersinia pestis, requires expression of the gene encoding the Pla protease for progression of pneumonic plague. The catabolite repressor protein Crp, a global transcriptional regulator, may serve as the activator of pla in response to changes within the lungs as disease progresses. By using gene reporter fusions, the spatial and temporal activation of the crp and pla promoters was measured in a mouse model of pneumonic plague. In the lungs, crp was highly expressed in bacteria found within large aggregates resembling biofilms, while pla expression increased over time independent of the aggregated state. Increased expression of crp and pla correlated with a reduction in lung glucose levels. Deletion of the glucose-specific phosphotransferase system EIIBC (PtsG) of Y. pestis rescued glucose levels in the lungs, resulting in reduced expression of both crp and pla We propose that activation of pla expression during pneumonic plague is driven by an increase of both Crp and cAMP levels following consumption of available glucose in the lungs by Y. pestis Thus, Crp operates as a sensor linking the nutritional environment of the host to regulation of virulence gene expression.IMPORTANCE Using Yersinia pestis as a model for pneumonia, we discovered that glucose is rapidly consumed, leading to a catabolite-repressive environment in the lungs. As a result, expression of the gene encoding the plasminogen activator protease, a target of the catabolite repressor protein required for Y. pestis pathogenesis, is activated. Interestingly, expression of the catabolite repressor protein itself was also increased in the absence of glucose but only in biofilms. The data presented here demonstrate how a bacterial pathogen senses changes within its environment to coordinate metabolism and virulence gene expression.

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A comprehensive analysis of blood host responses to Yersinia Pestis infection Temporal Progression of Pneumonic Plague in Blood of Nonhuman Primate: A Transcriptomic Analysis

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