Abstract
BackgroundGroup A streptococcal severe soft tissue infections, such as necrotizing fasciitis, are rapidly progressive infections associated with high mortality. Group A streptococcus is typically considered an extracellular pathogen, but has been shown to reside intracellularly in host cells.Methods and FindingsWe characterized in vivo interactions between group A streptococci (GAS) and cells involved in innate immune responses, using human biopsies (n = 70) collected from 17 patients with soft tissue infections. Immunostaining and in situ image analysis revealed high amounts of bacteria in the biopsies, even in those collected after prolonged antibiotic therapy. Viability of the streptococci was assessed by use of a bacterial viability stain, which demonstrated viable bacteria in 74% of the biopsies. GAS were present both extracellularly and intracellularly within phagocytic cells, primarily within macrophages. Intracellular GAS were predominantly noted in biopsies from newly involved tissue characterized by lower inflammation and bacterial load, whereas purely extracellular GAS or a combination of intra- and extracellular GAS dominated in severely inflamed tissue. The latter tissue was also associated with a significantly increased amount of the cysteine protease streptococcal pyrogenic exotoxin SpeB. In vitro studies confirmed that macrophages serve as reservoirs for viable GAS, and infection with a speB-deletion mutant produced significantly lower frequencies of cells with viable GAS following infection as compared to the wild-type bacteria.ConclusionsThis is the first study to demonstrate that GAS survive intracellularly in macrophages during acute invasive infections. This intracellular presence may have evolved as a mechanism to avoid antibiotic eradication, which may explain our finding that high bacterial load is present even in tissue collected after prolonged intravenous antibiotic therapy. This new insight into the pathogenesis of streptococcal soft tissue infections highlights a need for alternative therapeutic strategies.
Highlights
Severe invasive group A streptococcal diseases, including streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF), are rapidly progressive invasive diseases associated with significant morbidity and mortality [1,2]
In vitro studies confirmed that macrophages serve as reservoirs for viable group A streptococci (GAS), and infection with a speBdeletion mutant produced significantly lower frequencies of cells with viable GAS following infection as compared to the wild-type bacteria. This is the first study to demonstrate that GAS survive intracellularly in macrophages during acute invasive infections
This intracellular presence may have evolved as a mechanism to avoid antibiotic eradication, which may explain our finding that high bacterial load is present even in tissue collected after prolonged intravenous antibiotic therapy
Summary
Severe invasive group A streptococcal diseases, including streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF), are rapidly progressive invasive diseases associated with significant morbidity and mortality [1,2]. The study revealed distinct risk and protective human leukocyte antigen class II associations, depending on whether the patient had STSS or NF. One cause of a very severe soft infection called necrotizing fasciitis is a bacterium known as group A streptococcus. This infection can spread very quickly, and it can be fatal. They looked at 70 tissue samples taken from 17 people with soft tissue infections They found that many live bacteria were present both inside and outside of the cells that take up bacteria— one type of cell known as a macrophage—and even when the samples were taken after patients had had a long course of antibiotics. Experimental infections with bacteria that had this enzyme removed led to lower numbers of cells with living bacteria in them compared with the normal bacteria
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