Induced pluripotent stem cell-derived platelets kill multidrug-resistant Staphylococcus aureus via Toll-like receptor 2-MyD88 signaling and immunoglobulin G/FcγRIIA engagement.

BACKGROUND: Severe infection caused by multidrug-resistant bacteria, such as multidrug-resistant Staphylococcus aureus (MRSA), represents a pressing clinical challenge. While platelets are known to possess antibacterial activity against MRSA, the underlying mechanisms remain incompletely understood. In addition, the MRSA-killing capacity of induced pluripotent stem cell-derived platelets (iPSC-PLTs), which we succeeded in producing ex vivo, has not been previously characterized. OBJECTIVES: We aimed to verify whether iPSC-PLTs are capable of killing MRSA and further elucidate the mechanisms involved in this process. METHODS: We performed in vitro colony assays to assess MRSA killing by iPSC-PLTs. To gain mechanistic insights, we applied antiplatelet agents, an FcγRIIA-blocking antibody, α-toxin-deficient MRSA, and MyD88-deficient iPSC-PLTs, which we created by gene editing. RESULTS: All 3 iPSC-PLT clones demonstrated MRSA-killing capacity. Although only minimal activation of iPSC-PLTs was observed, antiplatelet agents inhibited this killing. Notably, plasma components enhanced the bactericidal activity of iPSC-PLTs, in part via immunoglobulin G, as evidenced by inhibition with an FcγRIIA-blocking antibody. Compared with wild-type MRSA, α-toxin-deficient strains were more susceptible to iPSC-PLT-mediated killing, suggesting that α-toxin acts as a suppressor of this platelet function. Furthermore, MyD88-deficient iPSC-PLTs exhibited impaired MRSA-killing capacity, indicating the indispensable role of Toll-like receptor 2-mediated signaling in this response. CONCLUSION: Collectively, our findings highlight the direct antimicrobial potential of iPSC-PLTs and provide mechanistic insights, particularly into the contribution of the Toll-like receptor-MyD88 axis. This study provided a basis for applying iPSC-PLTs as a novel therapeutic modality for combating MRSA infections and a genetically modifiable platform for investigating unknown platelet function within the context of antimicrobial immunity.