Abstract
The Gram-negative bacterium Burkholderia pseudomallei causes melioidosis and is a CDC category B bioterrorism agent. Toll-like receptor (TLR)-2 impairs host defense during pulmonary B.pseudomallei infection while TLR4 only has limited impact. We investigated the role of TLRs in B.pseudomallei-lipopolysaccharide (LPS) induced inflammation. Purified B.pseudomallei-LPS activated only TLR2-transfected-HEK-cells during short stimulation but both HEK-TLR2 and HEK-TLR4-cells after 24 h. In human blood, an additive effect of TLR2 on TLR4-mediated signalling induced by B.pseudomallei-LPS was observed. In contrast, murine peritoneal macrophages recognized B.pseudomallei-LPS solely through TLR4. Intranasal inoculation of B.pseudomallei-LPS showed that both TLR4-knockout(-/-) and TLR2x4-/-, but not TLR2-/- mice, displayed diminished cytokine responses and neutrophil influx compared to wild-type controls. These data suggest that B.pseudomallei-LPS signalling occurs solely through murine TLR4, while in human models TLR2 plays an additional role, highlighting important differences between specificity of human and murine models that may have important consequences for B.pseudomallei-LPS sensing by TLRs and subsequent susceptibility to melioidosis.
Highlights
The category B bioterrorism agent, as classified by the Center for Disease Control and Prevention, Burkholderia pseudomallei is a facultative intracellular Gram-negative bacterium and the causative agent of melioidosis [1,2,3]
We previously reported that a LPS compound derived from B.pseudomallei strain 1026b extracted by the hot aqueous-phenol method [20] was recognized by TLR2 and not TLR4 in Human Embryonic Kidney (HEK293) cells stably transfected with CD14, CD14-TLR2, or CD14-TLR4/MD-2 [21]
We established that TLR4 is the main receptor for LPS of B.pseudomallei in murine in vitro and in vivo models
Summary
The category B bioterrorism agent, as classified by the Center for Disease Control and Prevention, Burkholderia pseudomallei is a facultative intracellular Gram-negative bacterium and the causative agent of melioidosis [1,2,3]. TLR Recognition of B. pseudomallei-LPS pseudomallei, such as Burkholderia lethal factor 1, type III and VI secretion systems, capsular polysaccharide and flagella, lipopolysaccharide (LPS) stands out for its omnipresence and the high antibody titers which are generated against it in patients [4, 5]. In contrast to other Gram-negative pathogens, the LPS of B.pseudomallei is considered only weakly inflammatory [6]. In general LPS, which consists of lipid A, the core-oligosaccharide and the outer O-polysaccharide, plays an important role in cell integrity and in signalling to the host innate immune response [7, 8]
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