Physiopathologie des infections ostéo-articulaires liées aux Staphylococcus non-aureus

Abstract : Bone and joint infections (BJI) include several heterogeneous clinical entities that share the invasion and the progressive destruction of bone and cartilage tissue by one or more microorganisms. The genus Staphylococcus, involved in over 65% of the BJI, represents the first etiology in these particularly severe and difficult-to-treat infections. Staphylococcus non-aureus (SNA), including species such as Staphylococcus epidermidis, are responsible for nearly 40% of some clinical forms, including device-associated BJI. In contrast to S. aureus, for which pathophysiological mechanisms include (i) internalization capacity in host cells and (ii) biofilm formation, few data are available regarding those involved in BJIs due to SNA. In this context, my PhD work focused on characterizing the pathophysiological mechanisms involved in the genesis of BJI caused by different SNA species. Using an in silico together with an in vitro approach conducted in a human osteoblast invasion model, our work revealed an ability to internalize and persist in bone cells for only two species of SNA out of the 17 tested. Indeed, we have been able to demonstrate that only S. pseudintermedius and S. delphini have the ability to invade the cytoplasmic compartment of the host cells. Similar to S. aureus, the cellular invasion process for these species involves a tripartite association between bacterial adhesins fibronectin-binding proteins (FnBPs), fibronectin of the extracellular matrix, and α5β1 cell integrin. Another key point of this work is the demonstration of the highly cytotoxic phenotype of the S. pseudintermedius species after internalization in the host cells. We demonstrate here that this cytotoxicity is, at least in part, mediated by a combined action of (i) the Leukocidin Luk-I (homologous to S. aureus Panton-Valentine Leukocidin) that specifically targets immune cells expressing the CXC chemokine receptor 2 (CXCR2) with (ii) phenol-soluble modulins (PSMs) that disrupt the membranes of immune and non-immune cells. Knowing that SNA are the most incriminated infectious agents in device-associated BJI, a technique for studying biofilm on orthopedic biomaterials (stainless steel, titanium and polyethylene) has been developed to study the mature biofilm formed by the six SNA species with the highest prevalence in BJI (S. epidermidis, S. lugdunensis, S. heamolyticus, S. warneri, S. caprae, S. capitis). With the exception of S. epidermidis, which forms more biofilm on polyethylene (constituting at the interface of metal parts and / or bone in orthopedic prostheses), no significant difference was observed between the three orthopedic biomaterials for all the SNA species tested. The great diversity of phenotypes observed with respect to the pathophysiological mechanisms involved in BJI by the different SNA species tested demonstrates that SNA should not be considered as a single clinical entity. Improved knowledge provided during this work should contribute to the optimization of the surgical management, medical and therapeutic patient
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Yousef Maali. Physiopathologie des infections ostéo-articulaires liées aux Staphylococcus non-aureus. Microbiologie et Parasitologie. Université de Lyon, 2019. Français. ⟨NNT : 2019LYSE1091⟩. ⟨tel-02292813⟩

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