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    • It should be pointed out that the

    2018-11-09

    It should be pointed out that the study reported here has been conducted with a segment of ClfA and it is unclear if Fg binding to the full-length MSCRAMM can involve even more extensive interactions outside the N2N3 sub-domains. Our studies with tefibazumab have also revealed a novel inhibitory mechanism for the binding of ClfA to Fg. It is clear that the mechanism by which ClfA binds Fg is much more complex than previously appreciated and this complexity can at least partly explain the difficulty in generating effective anti-ClfA therapeutic agents including mAbs that can efficiently recognize natural ClfA variants from different strains of S. aureus. However, further characterization of the second binding site(s) may provide the opportunity to design sglt inhibitors and other molecules that interfere with both Fg-binding sites on ClfA to effectively inhibit this interaction that appears to be critical for S. aureus virulence (Josefsson et al., 2008).
    Conflicts of Interest
    Author Contributions
    Acknowledgements The work was supported in part by NIH grants AI020624 and HL119648, the Health Research Board of Ireland (RP 2004/1) and Science Foundation Ireland (08/1N.1/B1845). The structures reported here were derived using the data collected at GM/CA (Sector 23-ID). GM/CA@APS has been funded in whole or in part with Federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM-12006). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Dr. Emanuel Smeds for critical reading of the manuscript.
    Introduction Schistosomiasis is a neglected tropical and sub-tropical parasitic disease, caused by blood-dwelling fluke worms of the genus Schistosoma, affecting >230 million people worldwide (Colley et al., 2014). The primary pathology of schistosomiasis is egg-induced granuloma and fibrosis, which is a result of the host immune response to the eggs. In the early phase of infection, a type 1T-helper-cell (Th1) response is induced by the migration of the schistosomula and adult worms and is characterized by the elevation of interferon-γ (IFN-γ) levels. Host immune response is later polarized into a Th2 response, initiated by the release of eggs occurring 4–6weeks post-infection, featuring an increase in the levels of interleukin-4 (IL-4), IL-13, etc. (Pearce and MacDonald, 2002; Burke et al., 2009). These Th1 and Th2-related cytokines play a decisive role in the pathogenesis of schistosomiasis. Macrophages play a vital role in the liver pathology caused by Schistosoma (Barron and Wynn, 2011). They regulate the initiation, maintenance, and resolution of this chronic inflammatory disease and their function depends on their activation status. Macrophages can be classically activated (M1 macrophages) or alternatively activated (M2 macrophages) depending on the local immune environment (Kreider et al., 2007; Noël et al., 2004; Sica and Mantovani, 2012). M1 macrophages are induced by Th1 cytokines or microbial molecules such as lipopolysaccharide (LPS), while M2 macrophages are stimulated by Th2 cytokines. M1 macrophages primarily produce pro-inflammatory cytokines such as tumour necrosis factor α (TNF-α), IL-1β, IL-12, and IL-23. M2 macrophages are involved in Th2-biased response producing cytokines such as transforming growth factor β (TGF-β) and IL-10 leading to parasite clearance and host protection. MicroRNAs (miRNAs) are a class of endogenous, small noncoding RNA molecules, which control the translation and transcription of many genes (Bartel, 2004, 2009; Ma et al., 2011). Numerous studies have demonstrated that miRNAs play a crucial role in many human diseases including schistosomiasis (He et al., 2013, 2015; Cai et al., 2013, 2016; Han et al., 2013). Our previous study using miRNA microarrays demonstrated that a series of miRNAs were deregulated in the progression of hepatic schistosomiasis in a mouse model. Importantly, miR-21, one of the upregulated miRNAs, was involved in the regulation of activation of hepatic stellate cells (HSCs) and downregulation of miR-21 prevented lethal infection by repressing both TGF-β1 and IL-13 pathways (He et al., 2015).