Methicillin-resistant Staphylococcus aureus causes sustained collecting lymphatic vessel dysfunction

Area of Science:

• Infectious Diseases
• Immunology
• Vascular Biology

Background:

• Methicillin-resistant Staphylococcus aureus (MRSA) is a significant global health threat, causing morbidity and mortality, particularly through skin and soft tissue infections (SSTIs).
• Lymphedema, characterized by impaired lymphatic vessel function leading to tissue fluid accumulation, is a known risk factor for SSTIs and can also result from recurrent SSTIs, indicating a complex bidirectional relationship.
• The precise mechanisms underlying how SSTIs impact lymphatic vessel function, and vice versa, remain largely unknown.

Purpose of the Study:

• To investigate the impact of MRSA infection on lymphatic vessel function and identify the underlying molecular mechanisms.
• To determine if MRSA infection causes persistent lymphatic dysfunction even after the pathogen is cleared and inflammation subsides.
• To explore potential therapeutic targets for preserving lymphatic function during MRSA SSTIs.

Main Methods:

• Utilized intravital imaging in a mouse model to assess lymphatic vessel contractility and lymph flow following localized MRSA infection.
• Examined the structural integrity and function of lymphatic muscle cells (LMCs) in infected tissues.
• Conducted in vitro experiments exposing LMCs to MRSA-conditioned supernatant and employed proteomic analysis to identify MRSA virulence factors involved.
• Compared lymphatic function in mice infected with wild-type MRSA versus an accessory gene regulator (agr) mutant MRSA strain.

Main Results:

• MRSA infection caused an immediate decrease in lymphatic vessel contractility and lymph flow in mice.
• Lymphatic dysfunction persisted long after MRSA clearance and resolution of inflammation, associated with loss and disorganization of LMCs.
• MRSA-derived exotoxins, regulated by the accessory gene regulator (agr) system, were identified as mediators of LMC death in vitro.
• Mice infected with agr mutant MRSA exhibited preserved lymphatic function compared to those infected with wild-type MRSA.

Conclusions:

• MRSA infection directly impairs lymphatic vessel function through the killing of lymphatic muscle cells, mediated by agr-controlled exotoxins.
• This damage leads to chronic lymphatic impairment, highlighting a critical link between SSTIs and lymphedema.
• Targeting the MRSA agr system presents a promising strategy to maintain lymphatic vessel integrity and bolster host immunity during SSTIs.