Abstract
Unassisted metastasis through the lymphatic system is a mechanism of dissemination thus far ascribed only to cancer cells. Here, we report that Streptococcus pyogenes also hijack lymphatic vessels to escape a local infection site, transiting through sequential lymph nodes and efferent lymphatic vessels to enter the bloodstream. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and then efferent lymphatics that carry the bacteria through successive draining lymph nodes. We identify streptococcal virulence mechanisms important for bacterial lymphatic dissemination and show that metastatic streptococci within infected lymph nodes resist and subvert clearance by phagocytes, enabling replication that can seed intense bloodstream infection. The findings establish the lymphatic system as both a survival niche and conduit to the bloodstream for S. pyogenes, explaining the phenomenon of occult bacteraemia. This work provides new perspectives in streptococcal pathogenesis with implications for immunity.
Highlights
Unassisted metastasis through the lymphatic system is a mechanism of dissemination far ascribed only to cancer cells
Based on the lymphatic pathology associated with S. pyogenes disease and our recent discovery that the hyaluronan capsule of S. pyogenes binds the lymphatic endothelial hyaluronan receptor LYVE112,23, we hypothesised that the lymphatic system plays a central role in streptococcal pathogenesis in invasive infection
Draining lymph enters the bloodstream via the lymphatic ducts, and the surge in lymphatic bacterial burden at 3 h was accompanied by a similar surge in spleen bacterial load, an organ which removes bacteria from blood, providing clear evidence of S. pyogenes entry into the bloodstream25. 24 h post-infection, bacteraemia had increased from
Summary
Unassisted metastasis through the lymphatic system is a mechanism of dissemination far ascribed only to cancer cells. Contrasting with previously reported mechanisms of intracellular pathogen carriage by phagocytes, we show S. pyogenes remain extracellular during transit, first in afferent and efferent lymphatics that carry the bacteria through successive draining lymph nodes. We show that virulent S. pyogenes reach the first local draining lymph node, as demonstrated previously[12], but readily transit through sequential lymph nodes within efferent lymphatics to reach the bloodstream, while remaining extracellular. This lymphatic metastasis is a key pathway of dissemination that can drive bloodstream infection
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