B-4167. MyD88 Dependent Early Neutrophil Recruitment Contributes to Protective Host Defense Against Burkholderia Pseudomallei
Session: Slide Session: Immunobiology of Respiratory Infections
Tuesday, October 28, 2008: 12:00 AM
Room: Room 206
Background: Toll-like receptors (TLRs) have a central role in the recognition of pathogens and the initiation of the innate immune response. Myeloid differentiation primary-response gene 88 (MyD88) and TIR-domain-containing adaptor protein inducing IFNβ (TRIF) are regarded as the key signaling adaptor proteins for TLRs. Melioidosis, which is endemic in SE-Asia, is a severe infection caused by the gram-negative bacterium Burkholderia pseudomallei. We here aimed to characterize the role of MyD88 and TRIF in host defense against melioidosis. Methods: Responsiveness toward B. pseudomallei of MyD88 and TRIF deficient leukocytes compared to wild-type (WT) cells was tested in vitro. Additionally, in vivo we inoculated MyD88 knock-out (KO) and TRIF mutant mice with a lethal dose of B. pseudomallei. Results: MyD88, but not TRIF, deficient whole blood leukocytes released less TNFα upon stimulation with B. pseudomallei compared to WT cells. Furthermore, upon intranasal infection with B. pseudomallei MyD88 KO, but not TRIF mutant mice demonstrated a strongly accelerated lethality, which was accompanied by significantly increased bacterial loads in lungs, liver and blood, and grossly enhanced liver damage compared to WT mice. The decreased bacterial clearance capacity of MyD88 KO mice was accompanied by a markedly reduced early pulmonary neutrophil recruitment and a diminished activation of neutrophils after infection with B. pseudomallei. MyD88 KO leukocytes displayed an unaltered capacity to phagocytose and kill B. pseudomallei in vitro. Conclusions: MyD88 dependent signaling, but not TRIF dependent signaling, contributes to a protective host response against B. pseudomallei at least in part by causing early neutrophil recruitment towards the primary site of infection.
Catharina Wieland1, Joris Roelofs1, Tom van der Poll, MD PhD2, W. Wiersinga3 and  W. J. Wiersinga, None., (1)Academic Medical Center, University of Amsterdam, (2)Center of Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, Netherlands, (3)Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands