title: Triggering Receptor Expressed on Myeloid Cells (TREM)-2 Impairs Host Defense in Experimental Melioidosis.
abstract: Triggering receptor expressed on myeloid cells (TREM) -1 and TREM-2 are key regulators of the inflammatory response that are involved in the clearance of invading pathogens. Melioidosis, caused by the "Tier 1" biothreat agent Burkholderia pseudomallei, is a common form of community-acquired sepsis in Southeast-Asia. TREM-1 has been suggested as a biomarker for sepsis and melioidosis. We aimed to characterize the expression and function of TREM-1 and TREM-2 in melioidosis.
  
  
  
  Wild-type, TREM-1/3 (Trem-1/3-/-) and TREM-2 (Trem-2-/-) deficient mice were intranasally infected with live B. pseudomallei and killed after 24, and/or 72 h for the harvesting of lungs, liver, spleen, and blood. Additionally, survival studies were performed. Cellular functions were further analyzed by stimulation and/or infection of isolated cells. TREM-1 and TREM-2 expression was increased both in the lung and liver of B. pseudomallei-infected mice. Strikingly, Trem-2-/-, but not Trem-1/3-/-, mice displayed a markedly improved host defense as reflected by a strong survival advantage together with decreased bacterial loads, less inflammation and reduced organ injury. Cellular responsiveness of TREM-2, but not TREM-1, deficient blood and bone-marrow derived macrophages (BMDM) was diminished upon exposure to B. pseudomallei. Phagocytosis and intracellular killing of B. pseudomallei by BMDM and alveolar macrophages were TREM-1 and TREM-2-independent.
  
  
  
  We found that TREM-2, and to a lesser extent TREM-1, plays a remarkable detrimental role in the host defense against a clinically relevant Gram-negative pathogen in mice: TREM-2 deficiency restricts the inflammatory response, thereby decreasing organ damage and mortality.
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Tassili A F
authors.initials: TA
authors.lastname: Weehuizen
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Tijmen J
authors.initials: TJ
authors.lastname: Hommes
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Lankelma
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Hanna K
authors.initials: HK
authors.lastname: de Jong
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Department of Pathology, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.|Department of Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands.|Department of Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
mesh_terms: D000818:Animals; D016957:Burkholderia pseudomallei; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D007249:Inflammation / Q000378:metabolism; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D008554:Melioidosis / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C517262:TREM1 protein, mouse; C498716:Trem2 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1