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.

Increasing reports of invasive Streptococcus pyogenes infections mandate surveillance for toxigenic lineage M1 UK . An allele-specific PCR was developed to distinguish M1 UK from other emm 1 strains. The M1 UK lineage represented 91% of invasive emm 1 isolates in England in 2020. Allele-specific PCR will permit surveillance for M1 UK without need for genome sequencing.

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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 <i>Streptococcus pyogenes</i> 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.

Background. An increasing burden of invasive group A streptococcal infections is reported in multiple countries, notably England, where scarlet fever cases are also abundant. In England, increased scarlet fever and invasive infections have been associated with emergence of a sublineage of emm1 Streptococcus pyogenes that expresses increased SpeA scarlet fever erythrogenic toxin. Wider surveillance for toxigenic Streptococcus pyogenes lineage M1UK is much needed however, to date, lineage assignment has required genome sequencing limiting surveillance to those centres with access to such facilities. Methods. To circumvent the requirement for genome sequencing, an allele-specific PCR was developed to readily distinguish M1UK from other emm1 strains. Additional PCR assays were developed to distinguish M1UK from two intermediate lineages that were detected previously. The assay was evaluated using DNA from genome-sequenced upper respiratory tract emm1 S. pyogenes strains (n=31) and a further set of 16 genome-sequenced invasive S. pyogenes isolates that included the two intermediate lineages. The assay was then applied to DNA from all 305 invasive emm1 isolates that had been submitted to the reference laboratory in the one pear period Jan 1-Dec 31 2020, in order to assign lineage. Results. The allele specific PCR was 100% accurate when compared with genome sequencing, correctly identifying M1UK, two intermediate sublineages, and other emm1 strains. The assay demonstrated the M1UK lineage to be dominant among emm1 invasive isolates in England, representing 278/305 (91%) of invasive emm1 isolates by end of 2020. Implications. Emm1 S. pyogenes have a prominent role in invasive infections; any emm1 lineage that demonstrates enhanced fitness within the population is of public health concern. The allele specific PCR provides a readily available method to subtype emm1 isolates and does not require access to complex sequencing facilities. The data confirm that the M1UK lineage has persisted and further expanded in England underlining the importance of wider global surveillance.