Molecular alterations induced by Yersinia pestis, dengue virus and Staphylococcal enterotoxin B under severe stress

Abstract

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 to public health because of its implications for vaccine efficacy and treatment strategies during stressful scenarios. Severe stress has previously been shown to cause an anergic state in the immune system that persists following exposure to a potent mitogen.

Methods: Transcriptome and microRNA changes were characterized using blood samples collected from U.S. Army Ranger candidates immediately before and after training, followed by exposure to representative pathogenic agents: Yersinia pestis, dengue virus 2, and Staphylococcal enterotoxin B (SEB). We employed experimental and computational approaches to characterize altered gene expression, processes, pathways, and regulatory networks mediating the host's response towards severe stress; to assess the protective immunity status of the stressed host towards infection; and to identify pathogen-induced biomarkers under severe stress conditions.

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 demonstrated preservation of these pathways across infection and stress combinations. Regulatory networks comprising a common set of upstream regulators: transcription factors, microRNAs and post-translational regulators (kinases and phosphatases) may be drivers of molecular alterations leading to 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 pathogenic agent, forming specific molecular signatures with the potential to distinguish infection from that of severe stress.

Conclusions: Our results suggest that severe stress alters molecules implicated in the development of leukopoietic stem cells, thereby leading to depletion of cellular and molecular repertoires of protective immunity. Suppressed molecules mediating membrane trafficking of recycling endosomes, membrane translocation and localization of the antigen processing mechanisms and cell adhesions indicate suboptimal antigen presentation, impaired formation of productive immunological synapses, and inhibited T-cell activations. These factors may collectively be responsible for compromised protective immunity (infection susceptibility, delayed wound healing, and poor vaccine response) observed in people under severe stress.

Keywords: Biomarkers; Dengue virus; Gene expression; Immune response; Staphylococcal enterotoxin B (SEB); Stress; US Army Ranger Training Battalion (RASP: Rangers Assessment and Selection Program); Yersinia pestis (plague).