Methamphetamine promotes methicillin-resistant Staphylococcus aureus subcutaneous infection through innate immune dysregulation and altered expression of biofilm-associated genes.

Methamphetamine (METH) use is associated with an elevated risk of skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus (MRSA), yet its direct effects on MRSA pathogenesis remain poorly characterized. Using a BALB/c murine subcutaneous infection model, we demonstrate that METH significantly increases abscess area and bacterial burden compared to untreated controls. Histological analysis revealed markedly elevated neutrophil infiltration and a concurrent reduction in macrophage recruitment in METH-treated animals, indicating dysregulation of innate immune coordination at the infection site. METH exposure was also associated with increased expression of fga and col1, which are responsible for fibrinogen and collagen I production, respectively, consistent with profibrotic extracellular matrix remodelling that may scaffold bacterial persistence and impair immune effector access. At the molecular level, METH increased the expression of the icaA locus, which is required for polysaccharide intercellular adhesin synthesis and biofilm formation, compared to untreated MRSA-infected controls. Conversely, METH suppressed the sepA locus, suggesting a shift toward localized MRSA persistence within the abscess environment. Together, these results demonstrate that METH exacerbates MRSA subcutaneous infection in vivo through higher profibrotic host transcript levels, enhanced biofilm gene expression and dysregulated innate immunity. These findings provide a framework for future studies investigating how METH exposure shapes MRSA disease severity.