Abstract
BackgroundAt present, very little is known about how Burkholderia pseudomallei (B. pseudomallei) interacts with its host to elicit melioidosis symptoms. We established a murine acute-phase melioidosis model and used DNA microarray technology to investigate the global host/pathogen interaction. We compared the transcriptome of infected liver and spleen with uninfected tissues over an infection period of 42 hr to identify genes whose expression is altered in response to an acute infection.ResultsViable B. pseudomallei cells were consistently detected in the blood, liver and spleen during the 42 hr course of infection. Microarray analysis of the liver and spleen over this time course demonstrated that genes involved in immune response, stress response, cell cycle regulation, proteasomal degradation, cellular metabolism and signal transduction pathways were differentially regulated. Up regulation of toll-like receptor 2 (TLR2) gene expression suggested that a TLR2-mediated signalling pathway is responsible for recognition and initiation of an inflammatory response to the acute B. pseudomallei infection. Most of the highly elevated inflammatory genes are a cohort of "core host immune response" genes commonly seen in general inflammation infections. Concomitant to this initial inflammatory response, we observed an increase in transcripts associated with cell-death, caspase activation and peptidoglysis that ultimately promote tissue injury in the host. The complement system responsible for restoring host cellular homeostasis and eliminating intracellular bacteria was activated only after 24 hr post-infection. However, at this time point, diverse host nutrient metabolic and cellular pathways including glycolysis, fatty acid metabolism and tricarboxylic acid (TCA) cycle were repressed.ConclusionsThis detailed picture of the host transcriptional response during acute melioidosis highlights a broad range of innate immune mechanisms that are activated in the host within 24 hrs, including the core immune response commonly seen in general inflammatory infections. Nevertheless, this activation is suppressed at 42 hr post-infection and in addition, suboptimal activation and function of the downstream complement system promotes uncontrolled spread of the bacteria.
Highlights
At present, very little is known about how Burkholderia pseudomallei (B. pseudomallei) interacts with its host to elicit melioidosis symptoms
Very little is known about the molecular mechanisms that underlie B. pseudomallei virulence and how this organism is able to interact with its host to elicit melioidosis symptoms
Development and characterization of acute melioidosis in a mouse model BALB/c mice were challenged with three B. pseudomallei local clinical isolates via the intravenous (i.v.) route
Summary
Very little is known about how Burkholderia pseudomallei (B. pseudomallei) interacts with its host to elicit melioidosis symptoms. Very little is known about the molecular mechanisms that underlie B. pseudomallei virulence and how this organism is able to interact with its host to elicit melioidosis symptoms. Melioidosis can present with an array of clinical symptoms. Apparent infections range from acute or chronic localized infection involving a single organ, to fulminant septicaemia in multiple organs (liver, spleen, lung and prostate) and septic shock [1]. The factors influencing disease outcome are not known, it has been suggested that differences in the virulence of different infecting strains, the route of inoculation and inoculum size might contribute to the clinical outcome of disease [3]. The risk factor was extended to individuals who were uninjured bystanders during the tsunami of December 2004 [6]
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