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Bacteria possess the ability to evolve varied and ingenious strategies to outwit the host immune system, instigating an evolutionary arms race. Proteases are amongst the many weapons employed by bacteria, which specifically cleave and neutralize key signalling molecules required for a coordinated immune response. In this article, we focus on a family of S8 subtilisin-like serine proteases expressed as cell-envelope proteases (CEPs) by group A and group B streptococci. Two of these proteases known as Streptococcus pyogenes CEP (SpyCEP) and C5a peptidase cleave the chemokine CXCL8 and the complement fragment C5a, respectively. Both CXCL8 and C5a are potent neutrophil-recruiting chemokines, and by neutralizing their activity, streptococci evade a key defence mechanism of innate immunity. We review the mechanisms by which CXCL8 and C5a recruit neutrophils and the characterization of SpyCEP and C5a peptidase, including both in vitro and in vivo studies. Recently described structural insights into the function of this CEP family are also discussed. We conclude by examining the progress of prototypic vaccines incorporating SpyCEP and C5a peptidase in their preparation. Since streptococci-producing SpyCEP and C5a peptidase are responsible for a considerable global disease burden, targeting these proteases by vaccination strategies or by small-molecule antagonists should provide protection from and promote the resolution of streptococcal infections.

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., Pathogenic agents can spread from an initial to a secondary site via the lymphatics. Here, using a mouse model of infection, the authors show that S. pyogenes readily transit through sequential lymph nodes within efferent lymphatics to reach the bloodstream and drive systemic infection, while remaining extracellular.

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.