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Transcriptome characterization of immune suppression from battlefield-like stress

ABSTRACT: Transcriptome alterations of leukocytes from soldiers who underwent eight-weeks of Army Ranger training (RASP, Ranger Assessment and Selection Program) were analyzed to evaluate impacts of battlefield-like stress on the immune response. About 1,400 transcripts were differentially expressed between pre- and post-RASP leukocytes. Upon functional analysis, immune response was the most enriched biological process, and most of the transcripts associated with the immune response were down-regulated. Microbial pattern recognition, chemotaxis, antigen presentation, and T-cell activation were among the most down-regulated immune processes. Post-RASP leukocytes exposed ex vivo to Staphylococcal enterotoxin B (SEB) showed a markedly impaired immune response to this superantigen compared to pre-RASP leukocytes, consistent with suppression of the immune response revealed by transcriptome analyses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39148 | GEO | 2014/10/27

SECONDARY ACCESSION(S): PRJNA170109

REPOSITORIES: GEO

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Project description:Background: Severe stress can have drastic and systemic effects with dire implications on the health and wellbeing of exposed individuals. Particularly, the effect of stress on the immune response to infection is of interest because of its implications for vaccine efficacy and treatment strategy during stressful scenarios. Battlefield-like stress has previously been shown to cause an anergic state in the immune system that persists following exposure to a potent mitogen. Methods: Genome-wide alterations of gene expression were characterized using leukocytes collected from (15 informed and consented, all male) U.S. Army Ranger cadets immediately before and after training followed by exposure to a representative group of pathogens Yersinia pestis, dengue virus, Staphylococcus enterotoxin B (SEB). We employed experimental and computational approaches in identifying altered molecules, processes, pathways, and functional and regulatory networks mediating the host’s response towards battlefield-like stress, in assessing protective immunity status of the stressed host towards infection, and in identifying pathogen-induced biomarkers under severe stress background. Results: We observed predicted inhibition of pathways significantly associated with lymphopoiesis, wound healing, inflammatory response, lymphocyte activation, apoptosis, and predicted activation of oxidative stress. Using weighted correlation network analyses, we showed preservation of these pathways across infection plus stress combinations. Regulatory networks comprising a common set of upstream regulators: transcription factors, microRNAs and post-translational regulators (kinases, phosphatases) may be drivers of molecular alterations leading compromised protective immunity. Other sets of transcripts were persistently altered in both the pre- and post-stress conditions due to the host’s response to each pathogen forming pathogen-specific molecular signatures with a potential to distinguish infection from that of severe stress. Conclusion: Our results suggest that severe battlefield-like stress alters molecular players implicated in the developments of hematopoietic stem cells probably leading to depletion of cellular and molecular repertoires of protective immunity, membrane trafficking of recycling endosomes and membrane translocation of the antigen processing mechanisms leading to suboptimal antigen processing and presentation, cell adhesion leading to impaired formation of productive immunological synapse, and inhibited T-cell activation. These factors may collectively be responsible for compromised protective immunity (infection susceptibility, delayed wound healing and poor vaccine response), and cellular anergy.

Project description:Genome-wide alterations of gene expression were characterized using leukocytes collected from (informed and consented, all male) U.S. Army Ranger cadets immediately before and after training followed by exposure to a representative group of pathogens Yersinia pestis, dengue virus, Staphylococcus enterotoxin B. We employed experimental and computational approaches in identifying altered molecules, processes, pathways, and functional and regulatory networks mediating the host’s response towards battlefield-like stress, in assessing protective immunity status of the stressed host towards infection, and in identifying pathogen-induced biomarkers under severe stress background. We observed predicted inhibition of pathways significantly associated with lymphopoiesis, wound healing, inflammatory response, lymphocyte activation, apoptosis, and predicted activation of oxidative stress. Using weighted correlation network analyses, we showed preservation of these pathways across infection plus stress combinations. Regulatory networks comprising a common set of upstream regulators: transcription factors, microRNAs and post-translational regulators (kinases, phosphatases) may be drivers of molecular alterations leading compromised protective immunity. Other sets of transcripts were persistently altered in both the pre- and post-stress conditions due to the host’s response to each pathogen forming pathogen-specific molecular signatures with a potential to distinguish infection from that of severe stress. Our results suggest that severe battlefield-like stress alters molecular players implicated in the developments of hematopoietic stem cells probably leading to depletion of cellular and molecular repertoires of protective immunity, membrane trafficking of recycling endosomes and membrane translocation of the antigen processing mechanisms leading to suboptimal antigen processing and presentation, cell adhesion leading to impaired formation of productive immunological synapse, and inhibited T-cell activation. These factors may collectively be responsible for compromised protective immunity (infection susceptibility, delayed wound healing and poor vaccine response), and cellular anergy.

Project description:The species Staphylococcus (S.) aureus harbors 19 superantigen gene loci, six of which are located in the enterotoxin gene cluster (egc). While these egc superantigens are far more prevalent in clinical S. aureus isolates than non-egc superantigens, they are not a prominent cause of toxic shock. Moreover, neutralizing antibodies against egc superantigens are very rare, even among carriers of egc-positive S. aureus strains. In search of an explanation we have tested two non-exclusive hypotheses: 1) egc and non-egc superantigens have unique intrinsic properties and drive the immune system into different directions; 2) egc and non-egc-superantigens are released by S. aureus under different conditions, which shape the immune response. A comparison of three egc (SEI, SElM and SElO) and three non-egc superantigens (SEB, SElQ, TSST-1) revealed that both induced proliferation of human PBMC with comparable potency and elicited similar Th1/Th2-cytokine signatures. This was supported by gene expression analysis of PBMC stimulated with one representative superantigen from each group (SEI and SEB). They induced very similar transcriptional changes, especially of inflammation-associated gene networks, corresponding to a very strong Th1- and Th17-dominated immune response. In contrast, the regulation of superantigen release differed markedly between both superantigen groups. Egc-encoded proteins were secreted by S. aureus during exponential growth, while non-egc superantigens were released in the stationary phase. We conclude that the distinct biological behavior of egc and non-egc superantigens is not due to their intrinsic properties, which are very similar, but caused by their differential release by S. aureus. Experiment Overall Design: PBMCs from 3 healthy blood donors were purified and treated with Medium (control) and recombinant staphylococcal superantigens SEB and SEI. After 6 hours of treatment, total RNA was extracted and hybridized to Affymetrix GeneChip Arrays.

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Transcriptome characterization of immune suppression from battlefield-like stress

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