Playing With Fire: Proinflammatory Virulence Mechanisms of Group A Streptococcus

Abstract

Group A Streptococcus is an obligate human pathogen that is a major cause of infectious morbidity and mortality. It has a natural tropism for the oropharynx and skin, where it causes infections with excessive inflammation due to its expression of proinflammatory toxins and other virulence factors. Inflammation directly contributes to the severity of invasive infections, toxic shock syndrome, and the induction of severe post-infection autoimmune disease caused by autoreactive antibodies. This review discusses what is known about how the virulence factors of Group A Streptococcus induce inflammation and how this inflammation can promote disease. Understanding of streptococcal pathogenesis and the role of hyper-immune activation during infection may provide new therapeutic targets to treat the often-fatal outcome of severe disease.

Purinergic Signalling in Group A Streptococcus Pathogenesis

“…Secreted virulence factors are commonly associated with invasive inflammation and pathology ( 10 ). Streptococcal 5′-nucleotidase A (S5nA) is a secreted virulence factor and bacterial ectonucleotidase first identified in M1-expressing GAS ( 12 ).…”

“…Activation of P2X7 by extracellular ATP triggers the assembly of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome that activates caspases to stimulate pro-inflammatory interleukin (IL)-1β maturation and release ( 26 ). Since excessive cytokine release and hyperinflammation has been associated with both P2X7 activation ( 24 ) and invasive GAS pathologies ( 10 ), several studies have investigated a role for P2X7 in GAS infection.…”

“…Furthermore, nucleotides can modulate immune cell functions such as mTOR signalling and mitochondrial activation in neutrophils to regulate the chemotaxis of these cells ( 7 , 8 ), which have key roles in regulating GAS and other infections ( 9 ). Concurrent with purinergic receptor activation, a hyperinflammatory response is characteristic of invasive GAS infection ( 10 ), 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.…”

Antibiotic Treatment, Mechanisms for Failure, and Adjunctive Therapies for Infections by Group A Streptococcus

“…Some individuals are susceptible to recurring pharyngitis ( Dan et al, 2019 ), which may be prevented with tonsillectomy, although 33% of children lacking tonsils are still colonized by GAS ( Roberts et al, 2012 ). GAS exotoxins also promote colonization of the skin and more serious invasive infections and are major drivers of pathogenesis ( Wilde et al, 2021a ).…”

“…IVIG is generated from the pooled serum of healthy human donors and thus contains a panel of antibodies against diverse, but undefined, bacterial targets ( Schwab and Nimmerjahn, 2013 ). These likely include major toxins and surface-anchored virulence factors ( Wilde et al, 2021a ). Through their neutralization ( Parks et al, 2018 ) and increased opsonization of the bacterium, IVIG antibodies can decrease the bacterial burden and limit pro-inflammatory cytokine storms ( Figure 1 ; Kaul et al, 1999 ).…”