Purinergic Signalling in Group A Streptococcus Pathogenesis

Streptococcus pyogenes (Group A Streptococcus; GAS) is a human specific bacterial pathogen, recognised globally as one of the top ten leading causes of infectious disease mortality. It is responsible for causing a wide range of pathologies from superficial skin infections to invasive disease including necrotising fasciitis. Post-streptococcal sequelae, such as rheumatic heart disease, are severe complications that develop in response to repeated infections and are largely responsible for the global GAS-related death toll surpassing 500,000 fatalities annually. GAS expresses various virulence factors to subvert the host innate immune system, which is central to controlling GAS infection. Since current treatment strategies are failing, there is a need to further examine the (dys)regulation of host immune networks underlying GAS pathophysiology and identify novel therapeutic targets to arrest disease progression.

Purinergic signalling is an important immunomodulatory network in health and disease. In response to bacterial infections, damaged cells release adenosine 5′-triphosphate (ATP) and other nucleotides that can activate ionotropic P2X receptors and metabotropic P2Y receptors to promote a pro-inflammatory phenotype through cytokine production and immune cell recruitment. Cell surface ectonucleotidases, including CD39 and CD73, help arrest this pro-inflammatory response by hydrolysing exogenous ATP and adenosine 5’-diphosphate (ADP) to adenosine to restrict P2 receptor activation. This in turn stimulates metabotropic P1 (adenosine) receptors to promote an anti-inflammatory phenotype in immune and other cell types.

Several bacterial species can modulate the purinergic signalling network to enhance infection. Furthermore, nucleotides can modulate immune cell functions such as mTOR signalling and mitochondrial activation in neutrophils to regulate the chemotaxis of these cells, which have key roles in regulating GAS and other infections. Concurrent with purinergic receptor activation, a hyperinflammatory response is characteristic of invasive GAS infection, but current understanding of purinergic signalling mechanisms in GAS pathogenesis and host immunity remains limited. This opinion article provides a brief overview of current research data available on purinergic signalling in GAS infection and the potential of this signalling system as a therapeutic target in GAS infection.