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bioRxiv · 10.1101/530493

Necrotizing Soft-Tissue Infections-Staphylococcus aureus -but not Streptococcus pyogenes- isolates display high rate of internalization and cytotoxicity toward human myoblasts

Baude, J.·Bastien, S.·GILLET, Y.·Leblanc, P.·Itzek, A.·Tristan, A.·Bes, M.·Duguez, S.·Moreau, K.·Diep, B. A.·Norrby-Teglund, A.·Henry, T.·Vandenesch, F.
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Abstract

Necrotizing Soft Tissue Infections (NSTIs), often reaching the deep fascia and muscle, are mainly caused by group A Streptococcus (GAS) and to a lesser extent by Staphylococcus aureus (SA). Conversely SA is a leading etiologic agent of pyomyositis suggesting that SA could have a specific tropism for the muscle. To assess the pathogenicity of these two bacterial species for muscles cells in comparison to keratinocytes, adhesion and invasion of NSTI-GAS and NSTI-SA were assessed on these cells. Bloodstream infections (BSI) SA isolates and non-invasive coagulase negative Staphylococci (CNS) isolates were used as controls. SA isolates from NSTI and from BSI exhibited stronger internalization into human keratinocytes and myoblasts than CNS or NSTI-GAS. While the median level of SA internalization culminated at 2% in human keratinocytes, it reached over 30% in human myoblasts due to a higher percentage of infected myoblasts (>11%) as compared to keratinocytes (<3%) assessed by transmission electron microscopy. Higher cytotoxicity for myoblasts of NSTI-SA as compared to BSI-SA, was attributed to higher levels of psm and RNAIII transcripts in NSTI group as compared to hematogenous group. However, the two groups were not discriminated at the genomic level. The cellular basis of high internalization rate in myoblasts was attributed to higher expression of 5{beta}1 integrin in myoblasts as compared to keratinocytes. Major contribution of FnbpAB-integrin 5{beta}1 pathway to internalization was confirmed by isogenic mutants. Our findings suggest the contribution of NSTI-SA severity by its unique propensity to invade and kill myoblasts, a property not shared by NSTI-GAS. ImportanceNecrotizing Soft Tissue Infection (NSTI) is a severe infection caused mainly by group A Streptococcus (GAS) and occasionally by S. aureus (SA); the latter being more often associated with pyomyositis. NSTIs frequently involve the deep fascia and may provoke muscle necrosis. The goal of this study was to determine the tropism and pathogenicity of these two bacterial species for muscle cells. The results revealed a high tropism of SA for myoblasts and myotubes followed by cytotoxicity as opposed to GAS that did not invade these cells. This study uncover a novel mechanism of SA contribution to NSTI with a direct muscle involvement, while in GAS NSTI this is likely indirect, for instance, secondary to vascular occlusion.

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Baude, J., Bastien, S., GILLET, Y., Leblanc, P., Itzek, A., Tristan, A., Bes, M., Duguez, S., Moreau, K., Diep, B. A., Norrby-Teglund, A., Henry, T., Vandenesch, F.. 2019-01-28. Necrotizing Soft-Tissue Infections-Staphylococcus aureus -but not Streptococcus pyogenes- isolates display high rate of internalization and cytotoxicity toward human myoblasts. https://doi.org/10.1101/530493

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