Targeting phenol-soluble modulin α3-driven M1 macrophage polarization and necroptosis mitigates MRSA infection in mice
Year: 2026
Type: article
Abstract: The growing antibiotic resistance and high mortality rates associated with methicillin-resistant Staphylococcus aureus (MRSA) pose a global health threat, highlighting the urgent need for novel therapeutic strategies. Phenol-soluble modulin α3 (PSMα3) is a critical virulence factor in MRSA pathogenesis and immune evasion. However, its underlying mechanisms remain unclear. Here, we demonstrate that PSMα3 promotes both M1 macrophage polarization and necroptosis. These processes are mechanistically linked through an interaction between the interferon-stimulated gene factor 3 (ISGF3) and necrosome complexes, with formyl peptide receptor 2 (FPR2) serving as the key receptor. Based on this mechanism, we show that targeting signal transducer and activator of transcription 1 (STAT1), a key component of the ISGF3 complex, with the clinically approved drug fludarabine effectively mitigates MRSA infection in murine sepsis and pneumonia models. These findings reveal the mechanisms of MRSA pathogenesis and highlight the potential of anti-virulence strategies as innovative therapeutic approaches against MRSA infections. Methicillin-resistant Staphylococcus aureus (MRSA) is a key pathogenic bacterium and poses a significant therapeutic challenge due to its developing resistance to therapeutics. Here the authors establish a role for the MRSA virulence factor phenol-soluble modulin α3 in promoting macrophage M1 polarization and necroptosis via the host receptor FPR2 and the ISGF3 complex, and suggest the use of fludarabine to target the STAT1 component of this axis in models of MRSA infection.
Source: Nature Communications
Institution: Academy of Military Medical Sciences
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Award: G727510174
OpenAlex ID: W7141112055