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Study of proinflammatory responses induced by Yersinia pestis in human monocytes using cDNA arrays
1Department of Molecular Pathology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Abstract:
Yersinia pestis, the causative agent of plague, is known to develop strategies to overcome the host immune mechanisms and survive in the host. The molecular changes induced by Y. pestis in the host are not well delineated. Here, we examined the early events triggered after the intracellular infection of Y. pestis in human monocytes and lymphocytes by analyzing the host transcriptional profiles using cDNA arrays. We found that sets of genes that, especially at early time periods, were highly upregulated in monocytes alone when compared with a mixed culture of lymphocytes and monocytes. Gene expression responses revealed genes coding for cytokines, chemokines, transcription factors, inflammatory and apoptosis-related genes. Protein levels were measured, and real-time polymerase chain reaction was used to validate the microarray results. Our data suggest that intracellular infection of human monocytes with Y. pestis results in a strong inflammatory response at early time periods and a downregulation of genes such as thromobomodulin, which may play a role in coagulation, resulting in disseminated intravascular coagulation, a primary cause of death in plague infected hosts. We provide evidence that genomic analysis can provide a solid foundation to mechanistic insights to explain some of the symptoms induced by Y. pestis.
Insights
Yersinia pestis infection triggers a strong inflammatory response in human monocytes early on. This plague bacterium also downregulates genes involved in blood clotting, potentially leading to disseminated intravascular coagulation.
Area of Science:
- Immunology
- Molecular Biology
- Infectious Diseases
Background:
- Yersinia pestis causes plague and employs strategies to evade host immunity.
- The molecular mechanisms of Y. pestis pathogenesis are not fully understood.
- Understanding host responses is crucial for combating plague.
Purpose of the Study:
- To investigate the early molecular events following Yersinia pestis infection in human monocytes and lymphocytes.
- To identify host transcriptional changes induced by intracellular Y. pestis infection.
- To elucidate the mechanisms underlying plague symptoms.
Main Methods:
- Analysis of host transcriptional profiles using cDNA arrays after Yersinia pestis infection.
- Comparison of gene expression in monocytes versus mixed lymphocyte-monocyte cultures.
- Validation of microarray data using protein level measurements and real-time PCR.
Main Results:
- Significant upregulation of genes related to inflammation, cytokines, chemokines, transcription factors, and apoptosis in monocytes.
- Identification of downregulated genes, including thromobomodulin, crucial for coagulation.
- Early strong inflammatory response and potential disruption of coagulation pathways observed.
Conclusions:
- Intracellular Yersinia pestis infection induces a robust early inflammatory response in human monocytes.
- Downregulation of genes like thromobomodulin may contribute to disseminated intravascular coagulation, a hallmark of severe plague.
- Genomic analysis provides valuable mechanistic insights into Yersinia pestis-induced pathology.
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