Topical adjunctive treatment with flagellin augments pulmonary neutrophil responses and reduces bacterial dissemination in multidrug-resistant infection.

Objective: Antimicrobial resistance is an emerging problem and multi-drug resistant (MDR) () represents an enormous risk of failing therapy in hospital-acquired pneumonia. The current study aimed to determine the immunomodulatory effect of topical flagellin in addition to antibiotic treatment during respiratory infection evoked by hypervirulent antibiotic-susceptible and antibiotic-resistant in mice.

Methods: C57BL6 mice were inoculated intranasally with hypervirulent (K2:O1) which was either antibiotic-susceptible or multi-drug resistant.

The shifting lipidomic landscape of blood monocytes and neutrophils during pneumonia.

The lipidome of immune cells during infection has remained unexplored, although evidence of the importance of lipids in the context of immunity is mounting. In this study, we performed untargeted lipidomic analysis of blood monocytes and neutrophils from patients hospitalized for pneumonia and age- and sex-matched noninfectious control volunteers. We annotated 521 and 706 lipids in monocytes and neutrophils, respectively, which were normalized to an extensive set of internal standards per lipid class.

Immunostimulatory Effect of Flagellin on MDR--Infected Human Airway Epithelial Cells.

Pneumonia caused by multi-drug-resistant (MDR-) poses a major public health threat, especially to immunocompromised or hospitalized patients. This study aimed to determine the immunostimulatory effect of the Toll-like receptor 5 ligand flagellin on primary human lung epithelial cells during infection with MDR-. Human bronchial epithelial (HBE) cells, grown on an air-liquid interface, were inoculated with MDR- on the apical side and treated during ongoing infection with antibiotics (meropenem) and/or flagellin on the basolateral and apical side, respectively; the antimicrobial and inflammatory effects of flagellin were determined in the presence or absence of meropenem.

Host Response Changes and Their Association with Mortality in COVID-19 Patients with Lymphopenia.

Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release.

Thrombocytopenia is associated with a dysregulated host response in severe COVID-19.

Background: Thrombocytopenia is associated with increased mortality in COVID-19 patients.

Objective: To determine the association between thrombocytopenia and alterations in host response pathways implicated in disease pathogenesis in patients with severe COVID-19.

Patients/methods: We studied COVID-19 patients admitted to a general hospital ward included in a national (CovidPredict) cohort derived from 13 hospitals in the Netherlands.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown.

The Azithromycin Pro-Drug CSY5669 Boosts Bacterial Killing While Attenuating Lung Inflammation Associated with Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus.

Antibiotic resistance is a major problem, with methicillin-resistant Staphylococcus aureus (MRSA) being a prototypical example in surgical and community-acquired infections. S. aureus, like many pathogens, is immune evasive and able to multiply within host immune cells.

The host response in different aetiologies of community-acquired pneumonia.

Background: Community-acquired pneumonia (CAP) can be caused by a variety of pathogens, of which Streptococcus pneumoniae, Influenza and currently SARS-CoV-2 are the most common. We sought to identify shared and pathogen-specific host response features by directly comparing different aetiologies of CAP.

Methods: We measured 72 plasma biomarkers in a cohort of 265 patients hospitalized for CAP, all sampled within 48 hours of admission, and 28 age-and sex matched non-infectious controls.

Association between dexamethasone treatment and the host response in COVID-19 patients admitted to the general ward.

Dexamethasone improves clinical outcomes in COVID-19 patients requiring supplementary oxygen. We investigated possible mechanisms of action by comparing sixteen plasma host response biomarkers in general ward patients before and after implementation of dexamethasone as standard of care. 48 patients without and 126 patients with dexamethasone treatment were sampled within 48 h of admission.

Enrichment of Complement, Immunoglobulins, and Autoantibody Targets in the Proteome of Platelets from Patients with Systemic Lupus Erythematosus.

Background:  Systemic lupus erythematosus (SLE) is a complex disease characterized by autoimmunity toward apoptotic cells, excessive amounts of circulating immune complexes, and complement activation. A decreased platelet size has been observed in SLE and their nonhemostatic functions may play an active role in the disease. The main objective of this study was to find clues that could explain their decreased size and functional role, analyzing the entire platelet proteome.

Integrated single-cell analysis unveils diverging immune features of COVID-19, influenza, and other community-acquired pneumonia.

The exact immunopathophysiology of community-acquired pneumonia (CAP) caused by SARS-CoV-2 (COVID-19) remains clouded by a general lack of relevant disease controls. The scarcity of single-cell investigations in the broader population of patients with CAP renders it difficult to distinguish immune features unique to COVID-19 from the common characteristics of a dysregulated host response to pneumonia. We performed integrated single-cell transcriptomic and proteomic analyses in peripheral blood mononuclear cells from a matched cohort of eight patients with COVID-19, eight patients with CAP caused by Influenza A or other pathogens, and four non-infectious control subjects.

Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization.

Anti-neutrophil cytoplasmic antibody associated vasculitides (AAV) are conditions defined by an autoimmune small vessel inflammation. Dying neutrophils are found around the inflamed vessels and the balance between infiltrating neutrophils and macrophages is important to prevent autoimmunity. Here we investigate how sera from AAV patients may regulate macrophage polarization and function.

Increased synovial expression of nuclear receptors correlates with protection in pristane-induced arthritis: a possible novel genetically regulated homeostatic mechanism.

Objective: To use microarray analyses of gene expression to characterize the synovial molecular pathways regulated by the arthritis regulatory locus Cia25 and to determine how it operates to control disease severity and joint damage.

Methods: Synovial tissues from DA rats and DA.ACI(Cia25) rats obtained 21 days after induction of pristane-induced arthritis were used for RNA extraction and hybridization to Illumina RatRef-12 Expression BeadChips (22,228 genes).

Cutaneous scarring: a clinical review.

Cutaneous scarring can cause patients symptoms ranging from the psychological to physical pain. Although the process of normal scarring is well described the ultimate cause of pathological scarring remains unknown. Similarly, exactly how early gestation fetuses can heal scarlessly remains unsolved.

Purinergic receptors are part of a signalling system for proliferation and differentiation in distinct cell lineages in human anagen hair follicles.

We investigated the expression of P2X(5), P2X(7), P2Y(1) and P2Y(2) receptor subtypes in adult human anagen hair follicles and in relation to markers of proliferation [proliferating cell nuclear antigen (PCNA) and Ki-67], keratinocyte differentiation (involucrin) and apoptosis (anticaspase-3). Using immunohistochemistry, we showed that P2X(5), P2Y(1) and P2Y(2) receptors were expressed in spatially distinct zones of the anagen hair follicle: P2Y(1) receptors in the outer root sheath and bulb, P2X(5) receptors in the inner and outer root sheaths and medulla and P2Y(2) receptors in living cells at the edge of the cortex/medulla. P2X(7) receptors were not expressed.

P2X(5) and P2X(7) receptors in human warts and CIN-612 organotypic raft cultures of human papillomavirus infected keratinocytes.

Purinergic receptors, which bind adenosine 5'-triphosphate (ATP), are expressed on human cutaneous keratinocytes and in squamous cell carcinomas. Studies on normal human epidermis and primary keratinocyte cultures have suggested that P2X(5) receptors are likely to be involved in keratinocyte differentiation and P2X(7) receptors are likely to be part of the machinery of end stage terminal differentiation/apoptosis of keratinocytes. P2X(7) receptor agonists can significantly reduce primary keratinocyte cell numbers in culture.

In vitro optimisation of topical negative pressure regimens for angiogenesis into synthetic dermal replacements.

Background: The use of synthetic dermal replacements (SDRs) in the treatment of large wounds, which have associated morbidity and mortality, has attracted great interest. However, because of poor outcome, SDRs have limited use. The addition of topical negative pressure (TNP) has increased their success, but little research has focused on the underlying mechanisms.

Differential gene expression in response to transforming growth factor-beta1 by fetal and postnatal dermal fibroblasts.

The multipotent growth factor transforming growth factor (TGF)-beta1 is consistently linked with fibrosis and scarring. The perfect (scarless) healing of cutaneous wounds in early gestational age fetuses is proposed to be due to this tissue's predominance of the TGF-beta3 isoform over the profibrotic TGF-beta1 and 2. Nevertheless, TGF-beta1 is present during wound healing in the early fetus and recently we demonstrated that relevant intracellular signaling pathways are activated (albeit transiently) on TGF-beta1 stimulation.

Dermal fibroblasts derived from fetal and postnatal humans exhibit distinct responses to insulin like growth factors.

Background: It has been well established that human fetuses will heal cutaneous wounds with perfect regeneration. Insulin-like growth factors are pro-fibrotic fibroblast mitogens that have important roles in both adult wound healing and during development, although their relative contribution towards fetal wound healing is currently unknown. We have compared responses to IGF-I and -II in human dermal fibroblast strains derived from early gestational age fetal (<14 weeks) and developmentally mature postnatal skin to identify any differences that might relate to their respective wound healing responses of regeneration or fibrosis.

A role for TGF-beta1-induced cellular responses during wound healing of the non-scarring early human fetus?

Early human fetuses regenerate cutaneous wounds perfectly without scarring. However, transforming growth factor-beta1 (TGF-beta1), the cytokine linked with scarring in mature tissue, is also present during fetal wound repair, albeit transiently. We present a comparison of response to TGF-beta1 by fibroblasts derived from early human fetal skin (non-scarring) and their mature (scarring) postnatal counterparts, which revealed that although fetal fibroblasts do indeed differentiate into myofibroblasts, this response is altogether more rapid and short-lived.