Abstract
Background Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a kind of tropical disease. Burkholderia thailandensis (Bt), with a high sequence similarity to Bp, is thought to be an avirulent organism. Since there are numerous similarities between Bp and Bt, their differences in pathogenesis of host response and related mechanism are still undermined. In recent years, microRNAs have been researched in many diseases, but seldom involved in bacterial infection, bacteria-host interaction or explaining the differences between virulent and avirulent species.ResultsWe found that Bp and Bt had similar phenotypes in terms of intracellular replication, dissemination (reflected by multinucleated giant cell formation), TNF-α release and apoptosis in RAW264.7 macrophages or TC-1 pulmonary cell but in different level. Especially, at the late infection phases (after 12 h post infection), Bp showed faster intracellular growth, stronger cytotoxicity, and higher TNF-α release. After microRNA array analysis, we found some microRNAs were significantly expressed in macrophages treated by Bp. miR-3473 was one of them specifically induced, but not significantly changed in Bt-treated macrophages. In addition, TargetScan suggested that miR-3473 possibly target TRAF3 (TNF receptor-associated factor 3), a well-known negative regulator of the NF-κB pathway, which was probably involved in the TNF-α induction and apoptosis in cells with Bp infection. In vivo, it was found that miR-3473 expression of total lungs cells from Bp-treated was higher than that from Bt-treated mice. And miR-3473 inhibitor was able to decrease the TNF-α release of mice and prolong the survival of mice with Bp infection.ConclusionIn sum, miR-3473 plays an important role in the differential pathogenicity of Bp and Bt via miR-3473-TRAF3-TNF-α network, and regulates TNF-α release, cell apoptosis and animal survival after Bp treatment. In this study, we have found a specific microRNA is related to bacterial virulence and provide insight into the mechanism for host-bacteria interaction, which suggests that potential oligonucleotides should be applied against bacterial infection.
Highlights
Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a kind of tropical disease
A specific microRNA, miR-3473, has been identified to associate with the pathogenesis of Burkholderia pseudomallei in macrophages through a microRNA-TNF receptor-associated factor 3 (TRAF3)-TNF-α network, and influence the survival of mice with Bp infection through regulating TNF-α release
Though there may be other influence factors involved in differences between Bp and Burkholderia thailandensis (Bt), miR-3473 has provided a novel explanation and shed a light on the mechanism for bacterial infection from a view of microRNA
Summary
Burkholderia pseudomallei (Bp) is the causative agent of melioidosis, a kind of tropical disease. Bt has exhibited reduced replication in human macrophages and deficient invasion into epithelial cells compared to Bp [9, 10]. In vivo, it requires 2 × 102-fold more Bt by intranasal inoculation to infect and induce inflammation in C57BL/6 mice than Bp, and an inhalation model of Bt has been successfully established with an infection dosage of 3 × 104 cfu/lung [6]. Bt infections have been associated with human pulmonary cystic fibrosis [11, 12] To date, it needs more research into Bt or Bpspecific pathogenesis or mechanism for their different phenotypes
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