Gene expression following low dose inhalational Francisella tularensis (SchuS4) exposure in Balb/c mice and the potential role of the epithelium and cell adhesion

Abstract

Interactions between Francisella tularensis and the host are slowly being elucidated. Microarray technology was used to further characterise the response of Balb/c mice after inhalation of the virulent F. tularensis, SchuS4. The validated array data revealed changes in expression of 476 genes across a 96 h time course following infection (p ≤ 0.05). These data confirm down-regulation of the toll-like receptor pathway (TLR3, 4, 5, 7 and 8), and the induction of IFN-γ inducible genes (T-cell specific GTPase, β2 microglobulin and interleukin 21). The overall response appears to be two staged with an initial up-regulation of genes involved in apoptosis, TNFα production and antigen presentation. This is followed by a large alteration of expression at 96 h as the host succumbs to infection. A key regulatory time-point has been identified at 24 h post challenge, where several transcriptional events may predicate the progression of infection; these include transcriptional regulators of inflammation and proteolytic pathways. Pathway analysis indicates a novel role for cell–cell adhesion and extracellular matrix modulation in infection. Transcripts representing cellular junctions, focal adhesion and adherens junctions changed following infection. Additionally, aspects of extracellular matrix remodelling have been confirmed at the protein level, suggesting an important role of the respiratory epithelium in host response to F. tularensis warranting further study.