Lymphatic metastasis of virulent extracellular bacteria drives systemic infection

Lymphatic vessels carry fluid from tissues back to the bloodstream through filtering lymph nodes that limit infection and restrict passage of pathogens; ability to exploit these conduits is ascribed only to cancer cells and a small number of, principally intracellular, pathogens. Here, we report that Streptococcus pyogenes and other extracellular bacteria rapidly escape a local infection site and enter the blood circulation via the lymphatics, passing through sequential draining lymph nodes, and transiting in inter-nodal efferent lymphatic vessels, not blood vessels. Notably, S. pyogenes remain extracellular within lymphatic vessels and lymph nodes. By subverting innate immune responses to infection foci in lymph nodes, metastatic S. pyogenes replicate and seed intense bacteremia and systemic disease. Our findings identify extracellular lymphatic metastasis as the primary route of bacterial dissemination that provides both a survival niche and a conduit to reach the bloodstream and distant tissues for a range of bacteria.