Enhancing immunity by protecting lymphatic muscle cells from MRSA-Induced dysfunction

Infection-associated lymphatic vessel dysfunction contributes significantly to the pathogenesis and progression of lymphedema, a chronic disease characterized by impaired lymphatic vessel function and pathological fluid accumulation. Despite the recognized clinical correlation between recurrent skin and soft tissue infections, particularly those caused by Staphylococcus aureus (S. aureus), the molecular mediators and cellular mechanisms driving sustained lymphatic vessel dysfunction remain poorly defined. Our previous studies demonstrated that S. aureus infection leads to a reduction in lymphatic muscle cell (LMC) density, accompanied by morphological abnormalities in these cells. LMCs are integral to lymphatic vessel contractility, facilitating lymph propulsion and immune surveillance; disruption of LMC function leads to defective lymph flow and immune dysregulation, predisposing patients to recurrent infections and worsening lymphedema. Mechanistically, our previous work implicates bacterial toxins as direct modulators that impair lymphatic vessel function during infection. The proposed studies take an integrative approach to elucidate the infection-driven pathways that impair lymphatic vessel contractility and promote lymphedema progression. Aim 1 will characterize the molecular and cellular perturbations caused by S. aureus strains, utilizing single-cell transcriptomics and lineage tracing in murine models of cutaneous infection and lymphatic vessel dysfunction. This aim will delineate infection-associated signaling cascades and test the efficacy of pharmacological agents to restore contractile function of LMCs. Aim 2 focuses on evaluating the impact of S. aureus toxins on LMC calcium dynamics through high-resolution functional imaging. Additionally, the effect of targeted inhibition of S. aureus toxins on lymphatic function and host antimicrobial immunity will be investigated in vivo to determine their protective potential against recurrent infections. Successful completion of this project will identify novel therapeutic targets and strategies for preserving lymphatic vessel function, reducing lymphedema severity, and enhancing host defense mechanisms in infection-associated lymphatic vessel dysfunction.