Commentary: The Scavenger Receptor SSc5D Physically Interacts with Bacteria through the SRCR-Containing N-Terminal Domain

The recently published article by Bessa Pereira et al. reports that the human SSc5D receptor physically interacts with some bacterial species (1), thus basically confirming previous available information on its mouse homolog (S5D-SRCRB) (2). The interspecies conservation of such a basic innate immune function (bacterial binding) has been noticed for other members of the scavenger receptor cysteine-rich superfamily (SRCR-SF) (e.g., human Spα and its mouse homolog AIM/Api6/CD5L) (3, 4). This advocates for its functional physiological relevance in innate defense of body surfaces as it has been proposed for the urogenital tract (5). A substantive part of the work by Bessa Pereira et al. is also devoted to explore putative qualitative and/or quantitative differences on the bacterial-binding properties of SSc5D with other human SRCR-SF proteins, namely, CD5, Spα, and CD6 by using conventional protein-bacteria binding assays and surface plasmon resonance-based assays. They were chosen based on previously reported information showing that Spα (4) and CD6 (6-8) but not CD5 (9) exhibit broad bacterial-binding properties. While the authors confirmed the work on Spα and CD5, they were unable to replicate that on CD6. Exclusively based on a single experimental evidence, the authors cast doubt on the well-documented bacterial-binding properties of CD6 (6-8). These properties were unveiled by using a recombinant soluble form of human CD6 (rshCD6) encompassing from D25 to M400 and, indistinctly, produced in different mammalian cell expression systems (NSO, HEK293-EBNA, and CHO cells). Further confirmation was obtained by demonstrating similar properties displayed by a natural soluble CD6 form isolated from human serum, as well as by Jurkat cell transfectants expressing a membrane-bound full-length form of CD6 (6). Accordingly, it was later reported that rshCD6 infusion significantly reduces mouse mortality following septic shock induced by intraperitoneal monobacterial infection of Gram-positive (S. aureus) or Gram-negative (A. baumannii) origin (7). More recently, new evidence shows that not only rshCD6 but also adenovirally expressed mouse sCD6 have protective survival effects on polymicrobial septic shock induced by cecal ligation and puncture (8), the gold standard model for experimental sepsis

Genetic variants of innate immune receptors and infections after liver transplantation.

Infection is the leading cause of complication after liver transplantation, causing morbidity and mortality in the first months after surgery. Allograft rejection is mediated through adaptive immunological responses, and thus immunosuppressive therapy is necessary after transplantation. In this setting, the presence of genetic variants of innate immunity receptors may increase the risk of post-transplant infection, in comparison with patients carrying wild-type alleles. Numerous studies have investigated the role of genetic variants of innate immune receptors and the risk of complication after liver transplantation, but their results are discordant. Toll-like receptors and mannose-binding lectin are arguably the most important studied molecules; however, many other receptors could increase the risk of infection after transplantation. In this article, we review the published studies analyzing the impact of genetic variants in the innate immune system on the development of infectious complications after liver transplantation

Trends in Hospitalization of Patients with Potentially Serious Diseases Evaluated at a Quick Diagnosis Clinic

Although quick diagnosis units (QDU) have become a cost-effective alternative to inpatient admission for diagnosis of potentially serious diseases, the rate of return hospitalizations among evaluated patients is unknown. This study examined the temporal trends in admissions of QDU patients through 15 years. Adult patients referred to QDU from 2004 to 2019 who were hospitalized between the first and last visit in the unit were eligible. Decisions about admissions were mainly based on the Appropriateness Evaluation Protocol and required independent validation by experienced clinicians using a customized tool. The final analysis included 825 patients. Patient characteristics and major reasons for admission were compared each year and linear trends were analyzed. Admission rates decreased from 7.2% in 2004-2005 to 4.3% in 2018-2019 (p < 0.0001). While a significant increasing trend was observed in the rate of admissions due to cancer-related complications (from 39.5% in 2004-2005 to 61.7% in 2018-2019; p < 0.0001), those due to anemia-related complications and scheduled invasive procedures experienced a significant downward trend. A likely explanation for these declining trends was the relocation of the unit to a new daycare center in 2013-2014 with recovery rooms and armchairs for IV treatments. The facts of this study could help in the provision of anticipatory guidance for the optimal management of patients at risk of clinical complications

The ectodomains of the lymphocyte scavenger receptors CD5 and CD6 interact with tegumental antigens from Echinococcus granulosus sensu lato and protect mice against secondary cystic echinococcosis

Background: Scavenger Receptors (SRs) from the host's innate immune system are known to bind multiple ligands to promote the removal of non-self or altered-self targets. CD5 and CD6 are two highly homologous class I SRs mainly expressed on all T cells and the B1a cell subset, and involved in the fine tuning of activation and differentiation signals delivered by the antigen-specific receptors (TCR and BCR, respectively), to which they physically associate. Additionally, CD5 and CD6 have been shown to interact with and sense the presence of conserved pathogen-associated structures from bacteria, fungi and/or viruses. Methodology/Principal findings: We report herein the interaction of CD5 and CD6 lymphocyte surface receptors with Echinococcus granulosus sensu lato (s.l.). Binding studies show that both soluble and membrane-bound forms of CD5 and CD6 bind to intact viable protoscoleces from E. granulosus s.l. through recognition of metaperiodate-resistant tegumental components. Proteomic analyses allowed identification of thioredoxin peroxidase for CD5, and peptidyl-prolyl cis-trans isomerase (cyclophilin) and endophilin B1 (antigen P-29) for CD6, as their potential interactors. Further in vitro assays demonstrate that membrane-bound or soluble CD5 and CD6 forms differentially modulate the pro- and anti-inflammatory cytokine release induced following peritoneal cells exposure to E. granulosus s.l. tegumental components. Importantly, prophylactic infusion of soluble CD5 or CD6 significantly ameliorated the infection outcome in the mouse model of secondary cystic echinococcosis. Conclusions/Significance Taken together, the results expand the pathogen binding properties of CD5 and CD6 and provide novel evidence for their therapeutic potential in human cystic echinococcosis. Author summary: Scavenger Receptors (SRs) are constituents of host's innate immune system able to sense and remove altered-self and/or pathogen components. Data on their interaction with helminth parasites is scarce. In this work, we describe that CD5 and CD6 -two lymphoid SRs previously reported to interact with conserved structures from bacteria, fungi and viruses- recognize tegumental components in the cestode parasite Echinococcus granulosus sensu lato (s.l.). Moreover, both receptors differentially modulate the cytokine release by host cells exposed to E. granulosus s.l. tegumental components. Importantly, the infusion of soluble forms of CD5 or CD6 improve infection outcomes in a murine model of secondary cystic echinococcosis. In summary, our results expand the pathogen binding properties of CD5 and CD6 and suggest their therapeutic potential against helminth infections

Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights

IntroductionAntimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate.Methods and resultsThe Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity.DiscussionOverall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action

A C˄S-cyclometallated gold(III) complex as novel antibacterial candidate against drug-resistant bacteria

The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents

Impact of the functional CD5 polymorphism A471V on the response of chronic lymphocytic leukaemia to conventional chemotherapy regimens.

Chronic lymphocytic leukaemia (CLL) represents an abnormal clonal expansion of mature antigen-experienced CD5+ B1a cells (Chiorazzi et al, 2005), which present with a highly heterogeneous clinical course depending on associated chromosomal aberrations, somatic mutations within the immunoglobulin variable heavy chain genes (IGHV), and surface CD38 or intracytoplasmic ZAP-70 expression. Given that key signalling components of the B-cell receptor (BCR) are relevant contributors to the variable clinical behaviour of CLL (Stevenson et al, 2011) we explored the influence of functionally relevant germline CD5 variants on CLL prognosis

Gene variation at immunomodulatory and cell adhesion molecules Loci impacts primary Sjögren's Syndrome

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002T with anti-Ro/La positivity, CD6 rs17824933C with neutropenia, and CD6 rs11230563T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002T-rs2229177C) with anemia and thrombocytopenia, CD6 (rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585C-rs579565A-rs1044243C and rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pSS.Peer ReviewedPostprint (published version

Gene variation at immunomodulatory and cell adhesion molecules loci impacts primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) of CD5, CD6, and CD166/ALCAM with the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association of CD5 rs2241002T with anti-Ro/La positivity, CD6 rs17824933C with neutropenia, and CD6 rs11230563T with increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes from CD5 (rs2241002T-rs2229177C) with anemia and thrombocytopenia, CD6 (rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, and CD166/ALCAM (rs6437585C-rs579565A-rs1044243C and rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pS

CD5 and CD6 as immunoregulatory biomarkers in non-small cell lung cancer

Background: The study of immune surveillance in the tumour microenvironment is leading to the development of new biomarkers and therapies. The present research focuses on the expression of CD5 and CD6 - two lymphocyte surface markers involved in the fine tuning of TCR signaling - as potential prognostic biomarkers in resectable stages of non-small cell lung cancer (NSCLC). Methods: CD5 and CD6 gene expression was analysed by reverse transcription quantitative polymerase chain reaction (RTqPCR) in 186 paired fresh frozen tumour and normal tissue samples of resected NSCLC. Results: Patients with higher CD5 expression had significantly increased overall survival (OS, 49.63 vs. 99.90 months, p=0.013). CD5 expression levels were correlated to CD4 infiltration and expression levels, and survival analysis showed that patients with a higher CD5/CD4+ ratio had significantly improved prognosis. Multivariate analysis established CD5 expression as an independent prognostic biomarker for OS in early stages of NSCLC [HR=0.554; 95% CI, 0.360-0.853; p=0.007]. Further survival analysis of NSCLC cases (n=97) from The Cancer Genome Atlas (TCGA) database, confirmed the prognostic value of both CD5 and CD6 expression¸ although CD6 expression alone did not reach significant prognostic value in our NSCLC training cohort. Conclusions: Our data support further studies on CD5 and CD6 as novel prognostic markers in resectable NSCLC and other cancer types (i.e., melanoma), as well as a role for these receptors in immune surveillance