Lymphatic dissemination drives systemic invasion by diverse clinically relevant extracellular bacterial pathogens
Extracellular bacterial pathogens cause an estimated 6 million deaths annually and drive antimicrobial resistance. Systemic bacterial infection is typically attributed to direct blood vessel invasion or intracellular transit, while draining lymph nodes are generally assumed to trap and eliminate extracellular bacteria to prevent onward lymphatic spread. However, we previously demonstrated that Streptococcus pyogenes disseminates extracellularly via the lymphatic system. Here, we show that lymphatic dissemination extends across diverse clinically important extracellular bacterial pathogens, including Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus agalactiae. In a murine soft tissue infection model, clinical isolates reached local draining lymph nodes, sequential distant draining lymph nodes, and systemic organs. In contrast,non-draining lymph nodes contained few or no bacteria, even during bacteraemia, consistent with lymphatic spread rather than haematogenous seeding. Dissemination efficiency varied between species and among isolates, with S. aureus largely restricted to local draining lymph nodes. Notably, capsular polysaccharide enhanced lymphatic dissemination independently of bacterial burden at the infection site. These findings identify lymphatic dissemination as a common route of invasion by extracellular bacterial pathogens, exposing sequential draining lymph nodes to viable bacteria.