Abstract
BackgroundTriggering 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 FindingsWild-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/SignificanceWe 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.
Highlights
In sepsis, defined as a deregulated host response to a life-threatening infection, a careful balance between inflammatory and anti-inflammatory responses is vital [1,2,3]
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
Summary
In sepsis, defined as a deregulated host response to a life-threatening infection, a careful balance between inflammatory and anti-inflammatory responses is vital [1,2,3]. Pathogen- or danger-associated molecular patterns are recognized by intracellular sensory complexes and cell surface receptors expressed on innate immune cells that can initiate the inflammatory and anti-microbial response. A more recently discovered group of innate immune receptors are the membrane-bound triggering receptors expressed on myeloid cells (TREMs), which act as key modulators, rather than as initiators, of the inflammatory response [5,6,7]. In a murine pneumonia model of Legionella pneumonia no impact of TREM-1 deficiency was found on bacterial clearance or neutrophil influx towards the primary site of infection [18]. 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. We aimed to characterize the expression and function of TREM-1 and TREM-2 in melioidosis
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