Friday, May 16, 2025
5/16/2025
Role of TREM2 in host defense and immunity during infection - PROJECT SUMMARY Host defense and immunity are initiated by pattern-recognition receptor (PRR) binding to pathogen- or danger- associated molecular patterns. Activation of immune cells in response to microbes or damaged tissue results in the induction of antimicrobial processes, the production of inflammatory mediators, and activation of adaptive immunity. Triggering Receptor Expressed on Myeloid cells 2 (TREM2), is a scavenger receptor that is predominantly expressed on the surface of monocytes, macrophages, dendritic cells, and microglia. TREM2 binds to a diverse array of host and pathogen anionic molecules, including phospholipids, DNA, and lipoproteins, and contributes to sensing tissue damage. Given the myriad endogenous and microbial ligands that become accessible during tissue damage and infection, TREM2 activity in vivo is complex. Signaling through TREM2 in association with its adaptor protein DAP12 activates the tyrosine kinase Syk and can result in beneficial or detrimental outcomes for the host, depending on the context. Despite its broad expression on myeloid cells and its genetic association with neurodegenerative and metabolic diseases, the function of TREM2 in host defense and immunity during infection in vivo remains incompletely understood. Using a CRISPR knock-out strategy, we recently discovered a role for TREM2-DAP12-Syk signaling in human monocyte activation during infection with Toxoplasma gondii. We also found that TREM2 knock-out (KO) mice are acutely susceptible to T. gondii, with increased mortality and elevated parasite burden compared to control wild-type (C57BL/6) mice. These preliminary data support the hypothesis that TREM2 plays a key role in immunity against T. gondii. The objective of this proposal is to determine how TREM2 functions in human innate immunity and in protection against T. gondii in vivo using human immune cells and a mouse model. The first aim will examine the outcome of TREM2 activation in human immune responses by examining the signal transduction pathways that are activated and the production of cytokines and chemokines during infection or phagocytosis using control or TREM2 KO human monocytic cells and human induced pluripotent stem cell (iPSC)-derived microglia. The second aim will define the role of TREM2 in myeloid cell immunity in vivo by comparing antimicrobial host defense and protective immune responses during infection of myeloid- specific and microglia-specific TREM2 KO mice. The proposal involves the use of innovative single-cell proteomic technology and human iPSC-derived microglia. This research is significant because it has the potential to reveal a new receptor involved in innate immunity to T. gondii. In addition, an enhanced understanding of how TREM2 functions in the periphery and in microglia in the brain during infection may inform the development of strategies to increase its protective activities during disease.
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