Antibiotic biocompatibility assay and anti-biofilm strategies for Pseudomonas aeruginosa infection in bioengineered artificial skin substitutes.

Objectives: Bioengineered artificial skin substitutes (BASS) are an advanced therapy for treating extensively burned patients. Pseudomonas aeruginosa (P. aeruginosa) infections represent a major challenge in these patients as formation of biofilms impede wound healing and perpetuate a chronic inflammatory state.

Methotrexate promotes the release of granulocyte-macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling.

Background: Activated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators.

Antibiotics against on Human Skin Cell Lines: Determination of the Highest Non-Cytotoxic Concentrations with Antibiofilm Capacity for Wound Healing Strategies.

is one of the most common microorganisms causing infections of severe skin wounds. Antibiotic or antiseptic treatments are crucial to prevent and curb these infections. Antiseptics have been reported to be cytotoxic to skin cells and few studies evaluate the impact of commonly used antibiotics.

Immunomodulatory Nanoparticles for Modulating Arthritis Flares.

Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic--glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan and type 2 bovine collagen. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP).

Neutrophil-derived reactive agents induce a transient SpeB negative phenotype in Streptococcus pyogenes.

Background: Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection.

The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis.

Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory activity, including accumulation of naive-like CD45RACD62L ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lymphocytes.

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis.

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (T ) and suppression of T destabilization.

Systemic immune activation profiles in streptococcal necrotizing soft tissue infections: A prospective multicenter study.

Objective: Early stages with streptococcal necrotizing soft tissue infections (NSTIs) are often difficult to discern from cellulitis. Increased insight into inflammatory responses in streptococcal disease may guide correct interventions and discovery of novel diagnostic targets.

Methods: Plasma levels of 37 mediators, leucocytes and CRP from 102 patients with β-hemolytic streptococcal NSTI derived from a prospective Scandinavian multicentre study were compared to those of 23 cases of streptococcal cellulitis.

Targeted plasma proteomics reveals signatures discriminating COVID-19 from sepsis with pneumonia.

Background: COVID-19 remains a major public health challenge, requiring the development of tools to improve diagnosis and inform therapeutic decisions. As dysregulated inflammation and coagulation responses have been implicated in the pathophysiology of COVID-19 and sepsis, we studied their plasma proteome profiles to delineate similarities from specific features.

Methods: We measured 276 plasma proteins involved in Inflammation, organ damage, immune response and coagulation in healthy controls, COVID-19 patients during acute and convalescence phase, and sepsis patients; the latter included (i) community-acquired pneumonia (CAP) caused by Influenza, (ii) bacterial CAP, (iii) non-pneumonia sepsis, and (iv) septic shock patients.

Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function.

Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease.

The Karolinska KI/K COVID-19 Immune Atlas: An open resource for immunological research and educational purposes.

The Karolinska KI/K COVID-19 Immune Atlas project was conceptualized in March 2020 as a part of the academic research response to the developing SARS-CoV-2 pandemic. The aim was to rapidly provide a curated dataset covering the acute immune response towards SARS-CoV-2 infection in humans, as it occurred during the first wave. The Immune Atlas was built as an open resource for broad research and educational purposes.

Immunosuppressive Features of the Microenvironment in Lymph Nodes Granulomas from Tuberculosis and HIV-Co-Infected Patients.

Tuberculosis (TB) and HIV co-infection claims many lives every year. This study assessed immune responses in Mycobacterium tuberculosis-infected lymph node tissues from HIV-negative and HIV-positive patients compared with the peripheral circulation with a focus on myeloid cells and the cell-signaling enzymes, inducible nitric oxide synthase, and arginase (Arg)-1. Methods included immunohistochemistry or confocal microscopy and computerized image analyses, quantitative real-time PCR, multiplex Luminex, and flow cytometry.

COVID-19-specific metabolic imprint yields insights into multiorgan system perturbations.

Corona disease 2019 (COVID-19) affects multiple organ systems. Recent studies have indicated perturbations in the circulating metabolome linked to COVID-19 severity. However, several questions pertain with respect to the metabolome in COVID-19.

High-dimensional profiling reveals phenotypic heterogeneity and disease-specific alterations of granulocytes in COVID-19.

Since the outset of the COVID-19 pandemic, increasing evidence suggests that the innate immune responses play an important role in the disease development. A dysregulated inflammatory state has been proposed as a key driver of clinical complications in COVID-19, with a potential detrimental role of granulocytes. However, a comprehensive phenotypic description of circulating granulocytes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients is lacking.

Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections.

BACKGROUNDNecrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort.

Activated low-density granulocytes in peripheral and intervillous blood and neutrophil inflammation in placentas from SLE pregnancies.

Objective: Women with SLE face an increased risk of adverse pregnancy outcomes compared with healthy women, but the underlying immunological mechanisms are unknown. Given the recognised association of neutrophil activation with SLE pathogenesis, we examined whether there is increased neutrophil activation and inflammation in blood and placenta in SLE relative to healthy pregnancy.

Methods: At delivery, peripheral blood, maternal-derived intervillous blood and placentas were collected from 12 SLE and 10 healthy control pregnancies.

Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity.

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19.

Systems Biology and Biomarkers in Necrotizing Soft Tissue Infections.

In necrotizing soft tissue infection (NSTI) there is a need to identify biomarker sets that can be used for diagnosis and disease management. The INFECT study was designed to obtain such insights through the integration of patient data and results from different clinically relevant experimental models by use of systems biology approaches. This chapter describes the current state of biomarkers in NSTI and how biomarkers are categorized.

Pathogenic Mechanisms of Streptococcal Necrotizing Soft Tissue Infections.

Necrotizing skin and soft tissue infections (NSTIs) are severe life-threatening and rapidly progressing infections. Beta-hemolytic streptococci, particularly S. pyogenes (group A streptococci (GAS)) but also S.

The INFECT-Project: An International and Multidisciplinary Project on Necrotizing Soft Tissue Infections.

This book describes clinical and microbiologic aspects, pathogenesis, and diagnostics, related to the severe and rapidly spreading necrotizing soft tissue infections. The work has its foundation in a recently completed European Union funded FP7-project called INFECT, which during the period 2013-2018 focused on utilizing a systems medicine approach to increase our understanding of these heterogenous and complex life-threatening infections. In this chapter, the aim and scope as well as key achievements of the INFECT-project are described.

The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity.

The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E, IL-6, periostin, and leukemia inhibitory factor.