Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/36327
Title: MODULATION OF HOST NF¿B SIGNALING PATHWAYS BY BURKHOLDERIA PSEUDOMALLEI
Authors: TEH BOON ENG
Keywords: NFĸB, Burkholderia pseudomallei, melioidosis, TLR, NLR, T3SS3
Issue Date: 23-Aug-2012
Source: TEH BOON ENG (2012-08-23). MODULATION OF HOST NF¿B SIGNALING PATHWAYS BY BURKHOLDERIA PSEUDOMALLEI. ScholarBank@NUS Repository.
Abstract: Burkholderia pseudomallei is the causative agent of melioidosis and a highly versatile bacterium capable of invading non-immune cells such as epithelial cells. The routes of infection include inhalation or ingestion of the bacteria. When infection occurs via these routes, the mucosal epithelial cells likely form the first line of host defense. One of the main host defense mechanisms is pathogen detection via the major pattern recognition receptors termed the Toll-like receptors (TLRs). TLRs are highly expressed in immune cells but not in epithelial cells. Sensing of pathogens by TLRs mainly activates the NFkB pathway to initiate the host immune response. Using HEK293T cells as a model of epithelial cells, we found that HEK293T cells could sense the presence of wild type B. pseudomallei independently of TLRs and subsequently activate NFkB. This bacterial induced NFkB activation is independent of MyD88 but partially dependent on the NOD1 intracellular receptor that requires the action of Cdc42 and Rac1. The activation results in the phosphorylation of TAK1, IkBa and p65. On the other hand, NFkB activation by the wild type bacteria requires a functional Type Three Secretion Systems 3 (T3SS3) as the T3SS3 mutants failed to activate the pathway. The dependence on T3SS3 in NFkB activation is not due to activation by any of the known T3SS3 secreted effectors but due to the role of T3SS3 in facilitating early bacterial escape from endosomes to the cytosol, thereby being made accessible to host cytosolic sensors. The major T3SS3 structural component, BsaL also has a slight NFkB activating capability. This opens up the possibility that a novel bacterial component possessed only by pathogenic bacteria could be sensed directly by epithelial cells. While host cells could detect the presence of B. pseudomallei and activate NFkB as a host defense mechanism, B. pseudomallei has also evolved means to dampen this activation. A T3SS3 translocon BipB has been discovered to inhibit NFkB activation. Understanding how B. pseudomallei could trigger the activation of NFkB and concurrently inhibit the activation of NFkB reveal the tension constantly held between the host and pathogen. This study reveals novel strategies developed by both host and pathogen to outsmart each other by modulation of the host NFkB signaling pathway.
URI: http://scholarbank.nus.edu.sg/handle/10635/36327
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