Lymphatic dissemination is a major route of systemic invasion by diverse extracellular bacteria in soft tissue infection

Abstract

Extracellular bacterial pathogens cause substantial global mortality, yet how they disseminate from peripheral tissues into the bloodstream remains poorly understood. Systemic infection is typically attributed to direct vascular invasion, with draining lymph nodes considered terminal sites of containment. Here, using a murine soft-tissue infection model, we show that onward lymphatic dissemination from a distant tissue site through sequential draining lymph nodes is a major route of systemic invasion across diverse extracellular bacterial pathogens. Clinical isolates of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus pyogenes, and Streptococcus agalactiae spread from local draining lymph nodes to downstream lymph nodes and systemic organs. Non-draining lymph nodes, exposed to the same systemic circulation as downstream draining lymph nodes, contained markedly fewer bacteria even during bacteraemia, indicating lymphatic rather than haematogenous spread. Staphylococcus aureus was a notable exception, remaining largely restricted to local draining nodes with limited systemic spread. Deletion of the S. agalactiae capsular polysaccharide significantly reduced lymphatic and systemic spread without significantly reducing bacterial burden at the infection site, showing that capsule can promote lymphatic dissemination independently of local bacterial burden. In contrast, digestion of the secreted exopolysaccharide of P. aeruginosa did not alter dissemination, distinguishing the impact of surface-attached capsule from secreted exopolysaccharide. These findings establish lymphatic dissemination through sequential lymph nodes as a major invasion route across key extracellular bacterial pathogens, with important implications for systemic disease and immunity.