Alex F. de Vos, Tijmen J. Hommes, Marco Colonna, Tom van der Poll, Joris J. T. H. Roelofs, W. Joost Wiersinga, Tassili A. F. Weehuizen, Jacqueline M. Lankelma, Hanna K. de Jong, Other departments, Infectious diseases, Amsterdam institute for Infection and Immunity, Graduate School, Pathology, and Center of Experimental and Molecular Medicine
Background 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. Methodology/Principal Findings 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. Conclusions/Significance 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., Author Summary Triggering receptor expressed on myeloid cells (TREM)-1 and -2 are receptors on immune cells that act as mediators of the innate immune response. It is thought that TREM-1 amplifies the immune response, while TREM-2 acts as a negative regulator. Previously, we found that TREM-1 is upregulated in melioidosis patients. In contrast, nothing is known on TREM-2 expression and its role in melioidosis. In this study we examined the expression and functional role of both TREM-1 and -2 in a murine melioidosis model. We found that TREM-1 and-2 expression was upregulated during melioidosis. Using our experimental melioidosis model, we observed that Trem-2-/- mice were protected against B.pseudomallei-induced lethality. Trem-2-/- mice demonstrated reduced bacterial loads, inflammation and organ damage compared to wild-type mice in experimental melioidosis. Despite reduced bacterial dissemination of B.pseudomallei to distant organs in Trem-1/3-/ mice-, no differences in survival were found between Trem-1/3-/- and wild-type mice during melioidosis. Lastly, we investigated cellular functions of TREM-1 and TREM-2 and found that TREM-2 deficiency led to decreased cellular responsiveness to B. pseudomallei infection. In conclusion, we found that TREM-2 plays an important role during experimental murine melioidosis. TREM-2-deficiency reduces inflammation and organ damage, thereby improving survival.