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Role of the Yersinia pestis Virulence Plasmid in Evading a Protective Polymorphonuclear Leukocyte Response During the Early Stages of Bubonic Plague

ABSTRACT: A delay in the mammalian inflammatory response is a prominent feature of infection with Yersinia pestis, the agent of bubonic and pneumonic plague. Y. pestis factors have been identified that either do not stimulate a normal inflammatory response, or actively suppress it. Prominent among these are components of the Type III secretion system that is encoded on the Yersinia virulence plasmid (pYV). We used a rat model of bubonic plague to characterize the kinetics and extent of the mammalian transcriptomic response to infection with wild-type or pYV-negative Y. pestis in the draining lymph node. Remarkably, dissemination and multiplication of wild-type Y. pestis during the bubonic stage of disease did not induce any detectable gene expression response by host lymph node cells. This was followed, however, by an extensive transcriptomic response, including upregulation of several cytokine, chemokine, and other immune response genes, after systemic spread during septicemic plague. Matched lymph node samples used for histopathology and extracellular cytokine measurements, combined with the microarray data set, broadly outlined the mammalian immune response to Y. pestis and how it is influenced by pYV-encoded factors. The results indicate that both WT and pYV– Y. pestis induce primarily a Th17 response, and not a Th1 or Th2 response. In the absence of pYV, a sustained recruitment of polymorphonuclear leukocytes, the major Th17 effector cell, to the lymph node resulted in clearance of infection. Thus, the ability to counteract a Th17- driven PMN response in the lymph node appears to be a major function of the Y. pestis virulence plasmid. In contrast, classic markers of the proinflammatory response and macrophage activation, such as TNF-á and IFN-ã, were not induced at all by pYV– Y. pestis, and appeared only late in infection with WT Y. pestis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE22299 | GEO | 2010/12/07

SECONDARY ACCESSION(S): PRJNA127391

REPOSITORIES: GEO

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Project description:Initiation of treatment during the pre-symptomatic phase of infection with Yersinia pestis (Y. pestis) is particularly critical because the rapid proliferation of Y. pestis is coupled with the manifestation of common flu-like early symptoms that often delay the intervention. Our study used African Green Monkeys that didn’t exhibited clear clinical symptoms for nearly two days after intranasal challenge with Y. pestis and succumbed within a day after showing the first signs of clinical discomfort. Colonization of Y. pestis was detected in blood one day post-infection although blood transcripts were found to be altered immediately after the pathogenic assault. The organs of the respiratory tract and those adjacent, such as lungs and submandibular lymph nodes, accumulated significant Y. pestis colonization immediately after pathogenic challenge. Hence organ-specific molecular investigations are deemed to be the key in elucidation of the mechanisms of the initial host response. Based on results from our previous investigation of the blood transcriptomic profile, we explored the early involvement of the ubiquitin-microtubule-mediated host defense mechanism in detail. Genes enriching the ubiquitin network were altered, indicating an early suppression of the network functions in the submandibular lymph nodes. In concert, the upstream toll-like receptor signaling and downstream IκB kinase/NFκB signaling were inhibited at the transcription level. The inflammatory response was suppressed in the lungs, submandibular lymph nodes and mediastinal lymph nodes. By dysregulating both ubiquitin and the microtubule networks, Yersinia pestis was able to impair host-mediated proteolysis activities and evade autophagosome capture. A synchronized suppression of the immune response may render the peripheral organs more vulnerable to the imminent pathogenic assault. Furthermore, a comprehensive early onset of apoptosis was found across these three organ types. This was possibly a parallel mechanism undertaken by Yersinia pestis to further weaken the host response and enable a permissive colonization of the host. Targeting these networks in an organ-specific and time-resolved fashion could be essential for development of the next generation therapeutics for pneumonic plague.

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Role of the Yersinia pestis Virulence Plasmid in Evading a Protective Polymorphonuclear Leukocyte Response During the Early Stages of Bubonic Plague

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