Investigating a TREM2-TLR2 axis mediating Staphylococcus aureus infection 2329158

Abstract

Abstract Introduction Staphylococcus aureus can express a large arsenal of virulence factors, readily acquire antibiotic resistance, and survive harsh environmental conditions through biofilm formation. These traits facilitate evasion of host immunity and antibiotic killing, leading to chronic infections. A better understanding of pathogenicity and immune evasion are critical for more effective treatments. In a mouse model of S. aureus biofilm infection, we uncovered a critical role for triggering receptor expressed on myeloid cells-2 (TREM2) in exacerbating infection severity via anti-inflammatory responses to pathogen (PAMPs) and damage-associated molecular patterns (DAMPs). Interestingly, the role for TREM2 was specific to females, suggesting a role for estrogens. Further studies with bone marrow-derived macrophages showed that TREM2 loss enhanced surface expression of Toll-like receptor 2 (TLR2), a key immune receptor that senses bacterial lipoprotein and lipoteichoic acid for proinflammatory activation. Cross-regulation between TREM2, TLR2, and estrogens in the context of infection has not been described. Methods Mouse background (8-10 week old C57BL/6) and S. aureus (USA300 LAC-13C) strains were identical for all studies. Craniotomy infection was induced by inoculating bone flaps with 103 CFU. In vitro studies used primary bone marrow-derived macrophages. Flow cytometry (surface markers, metabolism, ROS/RNS), Cytometric Bead Array (mediator production), and Western blot (protein quantification) were also used. Results Macrophages with individual knockouts of TREM2 and TLR2, and a double knockout of TREM2/TLR2, showed cross-regulatory effects from these receptors and 17β-estradiol on inflammatory surface markers, mediator production, metabolism, and reactive oxygen/nitrogen species production. Conclusion TREM2, TLR2, and estrogen appear to have an interconnected role in driving immune responses, which could be exploited for moderating pro- vs anti-inflammatory immune activation during S. aureus infection. Funding Source Preliminary work was supported by NIH F32NS126302 to Lee Korshoj and R01NS107369 and R01AI169788 to Tammy Kielian. Current work is supported by startup funds from the University of Nebraska Medical Center to Lee Korshoj. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)