Molecular Pathogenesis of Necrotizing Fasciitis

Abstract

Necrotizing fasciitis, also known as the flesh-eating disease, is a severe invasive infection associated with very high rates of human morbidity and mortality. It is most commonly caused by group A Streptococcus(GAS), a versatile human pathogen that causes diseases ranging in severity from uncomplicated pharyngitis (or strep throat) to life-threatening infections such as necrotizing fasciitis. Herein, we review recent discoveries bearing on the molecular pathogenesis of GAS necrotizing fasciitis. Importantly, the integration of new technologies and the development of human-relevant animal models have markedly expanded our understanding of the key pathogen-host interactions underlying GAS necrotizing fasciitis. For example, we now know that GAS organisms secrete a variety of proteases that disrupt host tissue and that these proteolytic enzymes are regulated by multiple transcriptional and posttranslational processes. This pathogenesis knowledge will be crucial to supporting downstream efforts that seek to develop novel vaccines and therapeutic agents for this serious human infection.

Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences

“…The virulence of strains SF370 and MGAS2221 was assessed in pharyngitis and necrotizing fasciitis models, using cynomolgus macaques (Macaca fasicularis) (Charles River BRF), as previously described (44)(45)(46). Strains SF370 (n = 3 animals) or MGAS2221 (n = 4 animals) were used.…”

“…To directly test this hypothesis, we used two nonhuman primate models of infection to compare the virulence of preresurgence reference strain SF370 with postresurgence strain MGAS2221. The cynomolgus macaque has been used extensively for experimental studies because it closely approximates human-GAS molecular interactions (27,(44)(45)(46). Two groups of monkeys were infected in the upper respiratory tract with either strain SF370 or strain MGAS2221 and monitored for 21 d. Strain SF370 was used because it was the first GAS genome to be sequenced, has been used extensively in studies over the last 13 y, and contains the old variant of the 36-kb region of recombination.…”

“…We next tested the hypothesis that strain MGAS2221 was significantly more virulent during invasive infection, as assessed using a well-described nonhuman primate model of necrotizing fasciitis (27,44,45). Significantly more bacteria were recovered from animals infected with MGAS2221 compared with those infected with strain SF370 (Fig.…”

Impact of contusion injury on intramuscular emm1 group a streptococcus infection and lymphatic spread

“…Group A Streptococcus (GAS) is widely believed to seed contused tissue after blunt trauma injury [3,6,7]. Using a model of blunt injury with no external skin break, we were unable to demonstrate seeding of an invasive emm 1 isolate to injured muscle tissue using two models of systemic infection.…”

“…Many commentators have highlighted the role played by trauma in the development of invasive GAS infections, particularly necrotizing fasciitis [3,6,7], although the seeding of injured muscle tissue from respiratory tract has not been demonstrated experimentally. Previous studies have reported an effect of antecedent trauma on progression of invasive GAS infection [6,7], although we were unable to confirm specific seeding of contused tissue in our model.…”