Abstract
Shigella spp. are pathogenic bacteria that cause bacillary dysentery in humans by invading the colonic and rectal mucosa where they induce dramatic inflammation. Here, we have analyzed the role of the soluble PRR Pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity. Mice that had been intranasally infected with S. flexneri were rescued from death by treatment with recombinant PTX3. In vitro PTX3 exerts the antibacterial activity against Shigella, impairing epithelial cell invasion and contributing to the bactericidal activity of serum.PTX3 is produced upon LPS-TLR4 stimulation in accordance with the lipid A structure of Shigella. In the plasma of infected patients, the level of PTX3 amount only correlates strongly with symptom severity. These results signal PTX3 as a novel player in Shigella pathogenesis and its potential role in fighting shigellosis. Finally, we suggest that the plasma level of PTX3 in shigellosis patients could act as a biomarker for infection severity.
Highlights
The first line of immune defense against pathogens is guaranteed by the recognition of Pathogen Associated Molecular Patterns (PAMPs) by Pattern Recognition Receptors (PRRs)
Pentraxin 3 (PTX3) binds to virulent S. flexneri, affects Shigella epithelial cell invasion and macrophage internalization and contributes to serum bactericidal activity
We observed that PTX3 (50 μg/mL, 1,1 μM) opsonized the wild type S. flexneri 5 strain M90T (Fig 1A and 1B) and its plasmidless, non-invasive variant BS176 though to a lesser extent compared to P. aeruginosa, used as a positive control (12, 17)
Summary
The first line of immune defense against pathogens is guaranteed by the recognition of Pathogen Associated Molecular Patterns (PAMPs) by Pattern Recognition Receptors (PRRs). Shigella multiplies freely within the cytoplasm [4] where the cytosolic PRR Nod recognizes cell-wall peptidoglycan (PGN) and activates NF-κB [5,6]. S. flexneri changes its lipopolysaccharide (LPS) structure from a highly inflammatory hexa-acylated lipid A form to a less inflammatory tetra- and tri-acylated lipid A variant [8] This low-inflammatory LPS is poorly recognized by the PRR Toll-Like-Receptor 4 (TLR4), making macrophages and neutrophils less able to control the infection. In B lymphocytes Shigella induces TLR2-mediated apoptotic death through a mechanism mediated by T3SS, independent of cell invasion [9] These immune evasion strategies involve TLR2 and TLR4, which are PRRs present on the surface of many cell populations, suggesting that the extracellular step could be critical for successful infection. To gain insight about this poorly explored aspect of Shigella pathogenesis we analyzed the potential role of humoral PRRs, focusing on the possible involvement of Pentraxin 3 (PTX3), which has served as a paradigm of humoral innate immunity [10]
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