Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.

Interleukin-10 and the interleukin-10 receptor.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

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Myeloid-derived suppressor cells as regulators of the immune system.

The expanding universe of T-cell subsets: Th1, Th2 and more

Infectious Diseases Society of America.

Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host

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Pyroptosis: host cell death and inflammation

Objectives This study aimed to evaluate a cumulative antimicrobial resistance index (ARI) as a possible key outcome measure of antimicrobial stewardship programmes (ASPs) and a tool to predict the antimicrobial resistance (AMR) trend. Methods Antimicrobial susceptibility for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli (ESKAPEEc) pathogens recovered from blood cultures during a 5-year period (2014–2018) was analysed to obtain a cumulative ARI. For each antibiotic tested, a score of 0, 0.5 or 1 was assigned for susceptibility, intermediate resistance or resistance, respectively, and the ARI was calculated by dividing the sum of these scores by the number of antibiotics tested. Cumulative ARIs of ESKAPEEc micro-organisms were compared and a mathematical prediction model for AMR trend was obtained. Results In total, 1858 ESKAPEEc isolates were included in the study. The cumulative ESKAPEEc mean ARI increased significantly from 0.200 ± 0.01 in 2014 to 0.276 ± 0.02 in 2018 (P  Conclusion The ARI could be a useful tool to measure the impact of ASPs on AMR. The increasing incidence of AMR among ESKAPEEc organisms underscores the needing for ASPs.

Measurement and prediction of antimicrobial resistance in bloodstream infections by ESKAPE pathogens and Escherichia coli.

Infective endocarditis (IE) is a lifethreatening condition, in which identification of the causative pathogen is pivotal for subsequent effective therapy. Blood culture (BC) is considered the gold standard for microbiological diagnosis of IE (Watkin et al., 2003) but in up to one third of patients with suspected IE, BC can be negative due to a number of possible factors, such as prior antimicrobial therapy, the presence of fastidious microorganisms, or a low bacterial load (Lamas & Eykyn, 2003; Naber & Erbel, 2007). Identification of pathogens from heart valve tissue by real-time PCR has been shown to be a reliable technique (Lang et al., 2004; Mencacci et al., 2011). Several studies have demonstrated the diagnostic value of PCR in IE patients (Kühn et al., 2011; Zaloudı́ková et al., 2011), but few studies (Casalta et al., 2009) have evaluated the diagnostic utility of the commercially available PCR-based system SeptiFast (SF, Roche Diagnostics) for testing blood specimens. The SF system is able to detect and differentiate between a wide range of Gram-negative and Gram-positive bacteria, as well as some fungi, commonly involved in systemic infections (Lehmann et al., 2008). The aim of this study was to assess the diagnostic performance of the SF system, compared with BC, using blood specimens from patients with IE.

Diagnosis of infective endocarditis: comparison of the LightCycler SeptiFast real-time PCR with blood culture.

We studied the influence of cyclosporin-A (Cy-A) on resistance of mice to systemic infection with Candida albicans. Cy-A clearly inhibited resistance to C. albicans. The effect was dose-dependent and time and route of administration of the drug were important. This immunodepressive effect was due, at least in part, to an impairment of polymorphonuclear leucocyte (PMNL) candidacidal activity, as demonstrated in vitro by a reduction of phagocytic and cytotoxic activity and in vivo by protection when PMNL from untreated mice were transferred into cyclophosphamide-treated hosts challenged with C. albicans. The decreased activity of PMNL could be partly restored by adoptive transfer of normal T-lymphocytes into Cy-A-treated mice, as well as by exposure of PMNL to gamma-interferon (IFN-γ) in vitro.

Immunosuppressive effect of cyclosporin A on resistance to systemic infection with Candida albicans.

The major virulence factor of Cryptococcus neoformans is its capsular polysaccharide, which is also released into tissues. The shed polysaccharide is composed of glucuronoxylomannan, galactoxylomannan (GalXM), and mannoproteins. In a previous study, we demonstrated a direct interaction of purified soluble GalXM with T cells that induced their apoptosis. In this study, we focus on the mechanisms involved in the apoptotic effect of GalXM. In our experimental system, we analyzed the effect of GalXM on purified human T cells and Jurkat cells, a T cell line routinely used for apoptotic studies. Our results reveal that GalXM activates the extrinsic and intrinsic apoptotic pathways through the cleavage and recruitment of caspase-8. Caspase-8 elicits the downstream executioner caspase-3, caspase-6, and caspase-7 both directly and indirectly, via Bid cleavage and caspase-9 activation. These effects appeared to be primarily mediated by the interaction of GalXM with the glycoreceptors, which differed in human T and Jurkat cells. CD45 was primarily involved in Jurkat cells apoptosis while CD7 and CD43 mediated human T cell apoptosis. Our results highlight a new mechanism by which a microbial product can contribute to virulence through direct interaction with T cell glycoreceptors, thereby triggering lymphocyte apoptosis.

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Elio Cenci

Papers

Measurement and prediction of antimicrobial resistance in bloodstream infections by ESKAPE pathogens and Escherichia coli.

Diagnosis of infective endocarditis: comparison of the LightCycler SeptiFast real-time PCR with blood culture.

Immunosuppressive effect of cyclosporin A on resistance to systemic infection with Candida albicans.

Involvement of glycoreceptors in galactoxylomannan-induced T cell death

Low-dose streptozotocin-induced diabetes in mice. I. Course of Candida albicans infection.