Persistent Inflammatory Response Research Articles

DNA Origami Enhanced Cytokine Immunotherapy for Alleviating Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) is a major contributing factor to the development of acute kidney injury (AKI) and has resulted in considerable morbidity and mortality. Persistent inflammatory responses and excessive reactive oxygen species (ROS) in the kidney following IRI can severely delay tissue repair, making it challenging to effectively promote IRI regeneration. Herein, we report an approach to enhance immunotherapy using interleukin-10 (IL-10) to promote IRI regeneration by loading IL-10 onto rectangular DNA origami nanostructures (rDON). rDON can significantly enhance the renal accumulation and retention time of IL-10, enabling it to effectively polarize type 1 macrophages into type 2 macrophages, thereby significantly reducing proinflammatory factors and increasing anti-inflammatory factors. In addition, DNA origami helps mitigate the harmful effects of ROS during renal IRI. The administration of IL-10-loaded DNA origami effectively improves kidney function, resulting in a notable reduction in blood urea nitrogen, serum uric acid, and serum creatinine levels. Our study demonstrates that the integration of anti-inflammatory cytokines within DNA origami holds promise as a strategic approach for cytokine immunotherapy in patients with AKI and other renal disorders.

Increased levels of regulatory T cells and IL-10-producing regulatory B cells are linked to improved clinical outcome in Parkinson's disease: a 1-year observational study.

Whilst the contribution of peripheral and central inflammation to neurodegeneration in Parkinson's disease and the role of the immune response in this disorder are well known, the effects of the anti-inflammatory response on the disease have not been described in depth. This study is aimed to assess the changes in the regulatory/inflammatory immune response in recently diagnosed, untreated PD patients and a year after. Twenty-one PD patients and 19 healthy controls were included and followed-up for 1 year. The levels of immunoregulatory cells (CD4+ Tregs, Bregs, and CD8+ Tregs); classical, nonclassical, and intermediate monocytes, and proinflammatory cells (Th1, Th2, and Th17) were measured by flow cytometry. Cytokine levels were determined by ELISA. Clinical follow-up was based on the Hoehn & Yahr and UDPRS scales. Our results indicate that the regulatory response in PD patients on follow-up was characterized by increased levels of active Tregs, functional Tregs, TR1, IL-10-producing functional Bregs, and IL-10-producing classical monocytes, along with decreased counts of Bregs and plasma cells. With respect to the proinflammatory immune response, peripheral levels of Th1 IFN-γ+ cells were decreased in treated PD patients, whilst the levels of CD4+ TBET+ cells, HLA-DR+ intermediate monocytes, IL-6, and IL-4 were increased after a 1-year follow-up. Our main finding was an increased regulatory T cell response after a 1-year follow-up and its link with clinical improvement in PD patients. In conclusion, aftera 1-year follow-up, PD patients exhibited increased levels of regulatory populations, which correlated with clinical improvement. However, a persistent inflammatory environment and active immune response were observed.

Sex-based differences in persistent lung inflammation following influenza infection of juvenile outbred mice.

Children are susceptible to influenza infections and can experience severe disease presentation due to a lack of or limited pre-existing immunity. Despite the disproportionate impact influenza has on this population, there is a lack of focus on pediatric influenza research, particularly when it comes to identifying the pathogenesis of long-term outcomes that persist beyond the point of viral clearance. In this study, juvenile outbred male and female mice were infected with influenza and analyzed following viral clearance to determine how sex impacts the persistent inflammatory responses to influenza. It was found that females maintained a broader cytokine response in the lung following clearance of influenza, with innate, type I and type II cytokine signatures in almost all mice. Males, on the other hand, had higher levels of IL-6 and other macrophage-related cytokines, but no evidence of a type I or type II response. The immune landscape was similar in the lungs between males and females postinfection, but males had a higher regulatory T cell to TH1 ratio compared with female mice. Cytokine production positively correlated with the frequency of TH1 cells and exudate macrophages, as well as the number of cells in the bronchoalveolar lavage fluid. Furthermore, female lungs were enriched for metabolites involved in the glycolytic pathway, suggesting glycolysis is higher in female lungs compared with males after viral clearance. These data suggest juvenile female mice have persistent and excessive lung inflammation beyond the point of viral clearance, whereas juvenile males had a more immunosuppressive phenotype.NEW & NOTEWORTHY This study identifies sex-based differences in persistent lung inflammation following influenza infection in an outbred, juvenile animal model of pediatric infection. These findings indicate the importance of considering sex and age as variable in infectious disease research.

Effect of High Magnesium and Astragaloside IV on Vascular Endothelial Cells

Effect of High Magnesium and Astragaloside IV on Vascular Endothelial Cells

Multifunctional Hierarchical Nanoplatform with Anisotropic Bimodal Mesopores for Effective Neural Circuit Reconstruction after Spinal Cord Injury.

A persistent inflammatory response, intrinsic limitations in axonal regenerative capacity, and widespread presence of extrinsic axonal inhibitors impede the restoration of motor function after a spinal cord injury (SCI). A versatile treatment platform is urgently needed to address diverse clinical manifestations of SCI. Herein, we present a multifunctional nanoplatform with anisotropic bimodal mesopores for effective neural circuit reconstruction after SCI. The hierarchical nanoplatform features of a Janus structure consist of dual compartments of hydrophilic mesoporous silica (mSiO2) and hydrophobic periodic mesoporous organosilica (PMO), each possessing distinct pore sizes of 12 and 3 nm, respectively. Unlike traditional hierarchical mesoporous nanomaterials with dual-mesopores interlaced with each other, the two sets of mesopores in this Janus nanoplatform are spatially independent and possess completely distinct chemical properties. The Janus mesopores facilitate controllable codelivery of dual drugs with distinct properties: the hydrophilic macromolecular enoxaparin (ENO) and the hydrophobic small molecular paclitaxel (PTX). Anchoring with CeO2, the resulting mSiO2&PMO-CeO2-PTX&ENO nanoformulation not only effectively alleviates ROS-induced neuronal apoptosis but also enhances microtubule stability to promote intrinsic axonal regeneration and facilitates axonal extension by diminishing the inhibitory effect of extracellular chondroitin sulfate proteoglycans. We believe that this functional dual-mesoporous nanoplatform holds significant potential for combination therapy in treating severe multifaceted diseases.

DOES EXERCISE INFLUENCE CHRONIC INFLAMMATION IN BURNS >1 YEAR AFTER INJURY?

A burn is one of the most traumatic injuries a person can sustain, and along with mental and physical scars, trigger a greater and more persistent inflammatory and metabolic response than other trauma cases, with hypermetabolic and hyperinflammation being reported >3 years post-burn. Exercise has been shown to positively influence inflammatory and metabolic function in both healthy and diseased cohorts, however little is known about the influence of exercise on chronic inflammation and metabolism in burn survivors. The aim of this study was to determine the effects of an exercise intervention on inflammatory and metabolic markers in patients who had sustained a burn injury >1 year ago. In this study 15 participants were randomised in a cross over design into one of two conditions, either exercise-control, or control-exercise. The exercise condition comprised of six weeks of resistance and aerobic exercise, completed remotely or supervised in a hospital gym. A comprehensive battery of clinical and physiological assessments was completed at 0, 3 and 6 weeks of each exercise and control condition. The primary outcome measure for this study was TNF-alpha and how this changed in response to the exercise condition. Secondary measures included indirect calorimetry, metabolomic and lipidomic analysis, strength and aerobic fitness testing, body composition and questionnaires related to functional status and physical activity history. It is hoped that the results from this study will contribute to the future of post-burn rehabilitation and continue to develop the understanding surrounding the chronic post-response physiological response.

Nomogram predictive model for in-hospital mortality risk in elderly ICU patients with urosepsis

BackgroundUrinary tract infection (UTI) is a common cause of sepsis. Elderly patients with urosepsis in intensive care unit (ICU) have more severe conditions and higher mortality rates owing to factors such as advanced age, immunosenescence, and persistent host inflammatory responses. However, comprehensive studies on nomograms to predict the in-hospital mortality risk in elderly patients with urosepsis are lacking. This study aimed to construct a nomogram predictive model to accurately assess the prognosis of elderly patients with urosepsis and provide therapeutic recommendations.MethodsData of elderly patients with urosepsis were extracted from the Medical Information Mart for Intensive Care (MIMIC) IV 2.2 database. Patients were randomly divided into training and validation cohorts. A predictive nomogram model was constructed from the training set using logistic regression analysis, followed by internal validation and sensitivity analysis.ResultsThis study included 1,251 patients. LASSO regression analysis revealed that the Glasgow Coma Scale (GCS) score, red cell distribution width (RDW), white blood count (WBC), and invasive ventilation were independent risk factors identified from a total of 43 variables studied. We then created and verified a nomogram. The area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA) of the nomogram were superior to those of the traditional SAPS-II, APACHE-II, and SOFA scoring systems. The Hosmer-Lemeshow test results and calibration curves suggested good nomogram calibration. The IDI and NRI values showed that our nomogram scoring tool performed better than the other scoring systems. The DCA curves showed good clinical applicability of the nomogram.ConclusionsThe nomogram constructed in this study is a convenient tool for accurately predicting in-hospital mortality in elderly patients with urosepsis in ICU. Improving the treatment strategies for factors related to the model could improve the in-hospital survival rates of these patients.

Comparative analysis of endometrial, vaginal, and gut microbiota in patients with and without adenomyosis.

Alterations in microbiota composition have been implicated in a variety of human diseases. Patients with adenomyosis present immune dysregulation leading to a persistent chronic inflammatory response. In this context, the hypothesis that alterations in the microbiota may be involved in the pathogenesis of adenomyosis, by affecting the epigenetic, immunologic, and biochemical functions of the host, has recently been postulated. The aim of the present study was to compare the microbiota composition in the vagina, endometrium, and gut of individuals with and without adenomyosis. Cross-sectional study including 38 adenomyosis patients and 46 controls, performed between September 2021 and October 2022 in a university hospital-based research center. The diagnosis of adenomyosis was based on sonographic criteria. Fecal, vaginal, and endometrial samples were collected. Study of the microbiota using 16S rRNA gene sequencing. Patients with adenomyosis exhibited a significant reduction in the gut microbial alpha diversity compared with healthy controls (Chao1 p = 0.012, Fisher p = 0.005, Observed species p = 0.005). Beta-diversity analysis showed significant differences in the compositions of both gut and vaginal microbiota between adenomyosis patients and the control group (Adonis p-value = 0.001; R2 = 0.03 and Adonis p-value = 0.034; R2 = 0.04 respectively). Specific bacterial taxa were found to be either overrepresented (Rhodospirillales, Ruminococcus gauvreauii group, Ruminococcaceae, and Actinomyces) or underrepresented in the gut and endometrial microbiota of adenomyosis patients compared with controls. Distinct microbiota profiles were identified among patients with internal and external adenomyosis phenotypes. The study revealed reduced gut microbiota diversity in adenomyosis patients, accompanied by distinct compositions in gut and vaginal microbiota compared with controls. Overrepresented or underrepresented bacterial taxa were noted in the gut and endometrial microbiota of adenomyosis patients, with variations in microbiota profiles among those with internal and external adenomyosis phenotypes. These findings suggest a potential association between microbiota and adenomyosis, indicating the need for further research to comprehensively understand the implications of these differences.

Promoting the healing of diabetic wounds with an antimicrobial gel containing AgNPs with anti-infective and anti-inflammatory properties

Diabetic wounds are prone to develop chronic wounds due to bacterial infection and persistent inflammatory response. However, traditional dressings are monofunctional, lack bioactive substances, have limited bacterial inhibition as well as difficulties in adhesion and retention. These limit the therapeutic efficacy of traditional dressings on diabetic wounds. Therefore, finding and developing efficient and safe wound dressings is currently an urgent clinical need. In this study, an antimicrobial gel loaded with silver nanoparticles (AgNPs) (referred to as AgNPs@QAC-CBM) was prepared by crosslinking quaternary ammonium chitosan (QAC) with carbomer (CBM) as a gel matrix. AgNPs@QAC-CBM exhibited a reticulated structure, strong adhesion, good stability, and remarkable bactericidal properties, killing 99.9% of Escherichia coli, Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa within 1 min. Furthermore, AgNPs@QAC-CBM improved the wound microenvironment and accelerated wound healing in diabetic mice by promoting tissue production and collagen deposition, inducing M2 macrophages, reducing pro-inflammatory factor secretion and increasing anti-inflammatory factor levels. Moreover, AgNPs@QAC-CBM was proven to be safe for use through skin irritation and cytotoxicity tests, as they did not cause any irritation or toxicity. To summarize, AgNPs@QAC-CBM showed promising potential in enhancing the diabetic wound healing process.

Anti-inflammatory roles of type I interferon signaling in the lung.

Excessive or persistent inflammation may have detrimental effects on lung structure and function. Currently, our understanding of conserved host mechanisms that control the inflammatory response remains incompletely understood. In this study, we investigated the role of type I interferon signaling in the inflammatory response against diverse clinically relevant stimuli. Using mice deficient in type I interferon signaling (IFNAR1-/-), we demonstrate that the absence of interferon signaling resulted in a robust and persistent inflammatory response against Pseudomonas aeruginosa, lipopolysaccharide, and chemotherapeutic agent bleomycin. The elevated inflammatory response in IFNAR1-/- mice was manifested as elevated myeloid cells, such as macrophages and neutrophils, in the bronchoalveolar lavage. The inflammatory cell response in the IFNAR1-/- mice persisted to 14 days and there is impaired recovery and fibrotic remodeling of the lung in IFNAR1-/- mice after bleomycin injury. In the Pseudomonas infection model, the elevated inflammatory cell response led to improved bacterial clearance in IFNAR1-/- mice, although there was similar lung injury and survival. We performed RNA sequencing of lung tissue in wild-type and IFNAR1-/- mice after LPS and bleomycin injury. Our unbiased analysis identified differentially expressed genes between IFNAR1-/- and wild-type mice, including previously unknown regulation of nucleotide-binding oligomerization domain (NOD)-like receptor signaling, retinoic acid-inducible gene-I (RIG-I) signaling, and necroptosis pathway by type I interferon signaling in both models. These data provide novel insights into the conserved anti-inflammatory mechanisms of the type I interferon signaling.NEW & NOTEWORTHY Type I interferons are known for their antiviral activities. In this study, we demonstrate a conserved anti-inflammatory role of type I interferon signaling against diverse stimuli in the lung. We show that exacerbated inflammatory response in the absence of type I interferon signaling has both acute and chronic consequences in the lung including structural changes.

Antibacterial and DNA-Based Hydrogels In Situ Block TNF-α to Promote Diabetic Alveolar Bone Rebuilding.

Alveolar bone injury under diabetic conditions can severely impede many oral disease treatments. Rebuilding diabetic alveolar bone in clinics is currently challenging due to persistent infection and inflammatory response. Here, an antibacterial DNA-based hydrogel named Agantigel is developed by integrating silver nanoclusters (AgNCs) and tumor necrosis factor-alpha (TNF-α) antibody into DNA hydrogel to promote diabetic alveolar bone regeneration. Agantigel can effectively inhibit bacterial growth through AgNCs while exhibiting negligible cytotoxicity in vitro. The sustained release of TNF-α antibody from Agantigel effectively blocks TNF-α and promotes M2 polarization of macrophages, ultimately accelerating diabetic alveolar bone regeneration in vivo. After 21 days of treatment, Agantigel significantly accelerates the defect healing rate of diabetic alveolar bone up to 82.58±8.58% and improves trabecular architectures compared to free TNF-α (42.52±15.85%). The results imply that DNA hydrogels are potential bio-scaffolds helping the sustained release of multidrug for treating DABI or other oral diseases.

Abstract 146: Trained Immunity Induced by Dietary Salt Impedes Long-Term Brain Recovery in Experimental Intracerebral Hemorrhage

Introduction: Excessive sodium intake is the top dietary risk factor for mortality and non-communicable diseases such as stroke. However, whether and how a high salt diet (HSD) impacts long-term stroke outcomes - even after salt reduction/withdrawal prior to a stroke is unknown. Methods: Intracerebral hemorrhage (ICH) was modeled by blood or collagenase injections in mice. Bone marrow (BM) progenitor and immune cell compositions as well as monocyte-derived macrophage (MDM) and microglial phenotypes were profiled using flow cytometry. BM chimeras were created to test innate immune memory. Glycolysis and OXPHOS were measured by Seahorse assays. Macrophage phagocytosis was evaluated using in vivo and in vitro erythrophagocytosis assays. RNA-seq was used to analyze the progenitor transcriptome. Hematoma, neuron loss, and astrogliosis were assessed with immunofluorescence. LysM Cre/+ : NR4a1 fl/fl ; Nr4a2 fl/fl ; NR4a3 -/- mice, LysM Cre/+ : NR4a1 fl/fl mice, and celastrol treatment were used to elucidate the mechanism underlying HSD-induced trained immunity. Results: HSD impaired long-term ICH recovery despite prior salt withdrawal. HSD triggered innate immune training in BM progenitor cells by downregulating the NR4a family and OXPHOS. This training selectively compromised MDM reparative polarization without altering their initial inflammatory response in the ICH brain. Healthy mice transplanted with BM from HSD-fed mice retained training signatures, confirming a persistent form of trained immunity that originates in the BM. Lack of NR4a1 in MDMs recapitulated HSD-induced negative impacts on ICH outcomes. Notably, transplantation of healthy BM and gain of NR4a1 function enabled stroke recovery in the HSD animals. Conclusions: These findings provide the first evidence that links HSD-induced trained immunity to the acquisition of persistent dysregulated inflammatory responses and unveil NR4a1 as a potential therapeutic target.

Inhibitory effect of doxycycline conjugated with deoxycholic acid and polyethylenimine conjugate on nasal fibroblast differentiation and extracellular production.

Chronic rhinosinusitis (CRS) is an inflammatory disease affecting the sinuses or nose. Persistent inflammatory responses can lead to tissue remodeling, which is a pathological characteristics of CRS. Activation of fibroblasts in the nasal mucosal stroma, differentiation and collagen deposition, and subepithelial fibrosis have been associated with CRS. We aimed to assess the inhibitory effects of doxycycline and deoxycholic acid-polyethyleneimine conjugate (DA3-Doxy) on myofibroblast differentiation and extracellular matrix (ECM) production in nasal fibroblasts stimulated with TGF-β1. To enhance efficacy, we prepared DA3-Doxy using a conjugate of low-molecular-weight polyethyleneimine (PEI) (MW 1800) and deoxycholic acid (DA) and Doxy. The synthesis of the DA3-Doxy polymer was confirmed using nuclear magnetic resonance, and the critical micelle concentration required for cationic micelle formation through self-assembly was determined. Subsequently, the Doxy loading efficiency of DA3 was assessed. The cytotoxicity of Doxy, DA3, PEI, and DA-Doxy in nasal fibroblasts was evaluated using the WST-1 assay. The anti-tissue remodeling and anti-inflammatory effects of DA3-Doxy and DA3 were examined using real-time polymerase chain reaction (Real-time PCR), immunocytochemistry, western blot, and Sircol assay. Both DA3 and DA3-Doxy exhibited cytotoxicity at 10 μg/ml in nasal fibroblasts. Doxy partially inhibited α-smooth muscle actin, collagen types I and III, and fibronectin. However, DA3-Doxy significantly inhibited α-SMA, collagen types I and III, and fibronectin at 5 μg/ml. DA3-Doxy also modulated TGF-β1-induced changes in the expression of MMP 1, 2, and 9. Nonetheless, TGF-β1-induced expression of MMP3 was further increased by DA3-Doxy. The expression of TIMP 1 and 2 was partially reduced with 5 μg/ml DA3-Doxy. Although initially developed for the delivery of genetic materials or drugs, DA3 exhibits inhibitory effects on myofibroblast differentiation and ECM production. Therefore, it holds therapeutic potential for CRS, and a synergistic effect can be expected when loaded with CRS treatment drugs.

Targeting Interleukin-17 as a Novel Treatment Option for Fibrotic Diseases.

Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed world. Until recently, there were no approved antifibrotic therapies. In recent years, high levels of interleukin-17 (IL-17) have been associated with chronic inflammatory diseases with fibrotic complications that culminate in organ failure. In this review, we provide an update on the role of IL-17 in fibrotic diseases, with particular attention to the most recent lines of research in the therapeutic field represented by the epigenetic mechanisms that control IL-17 levels in fibrosis. A better knowledge of the IL-17 signaling pathway implications in fibrosis could design new strategies for therapeutic benefits.

CCL5's Role in Periodontal Disease: A Narrative Review.

Persistent host inflammatory and immune responses to biofilm play a critical role in the mechanisms that govern soft and hard tissue destruction in periodontal disease. Among the less explored facets of these mechanisms are chemokines, including CCL5 (C-C motif chemokine ligand 5), also known as RANTES (regulated on activation, normal T cell expressed and secreted), a proinflammatory CC subfamily chemokine synthesized by T lymphocytes. Despite its importance, there is currently no comprehensive review of the role of CCL5 in periodontitis in the literature. Therefore, this paper aims to fill this gap by summarizing the existing knowledge on the involvement of CCL5 in the onset and progression of periodontitis. In addition, we aim to stimulate interest in this relatively overlooked factor among periodontitis researchers, potentially accelerating the development of drugs targeting CCL5 or its receptors. The review examines the association of CCL5 with periodontitis risk factors, including aging, cigarette smoking, diabetes, and obesity. It discusses the involvement of CCL5 in pathological processes during periodontitis, such as connective tissue and bone destruction. The data show that CCL5 expression is observed in affected gums and gingival crevicular fluid of periodontitis patients, with bacterial activity contributing significantly to this increase, but the reviewed studies of the association between CCL5 expression and periodontal disease have yielded inconclusive results. Although CCL5 has been implicated in the pathomechanism of periodontitis, a comprehensive understanding of its molecular mechanisms and significance remains elusive, hindering the development of drugs targeting this chemokine or its receptors.

Research progress on anti-inflammatory effects of plant-derived cannabinoid type 2 receptor modulators

Excessive and persistent inflammatory responses are a potential pathological condition that can lead to diseases of various systems, including nervous, respiratory, digestive, circulatory, and endocrine systems. Cannabinoid type 2 receptor(CB2R) belongs to the G protein-coupled receptor family and is widely distributed in immune cells, peripheral tissues, and the central nervous system. It plays a role in inflammatory responses under various pathological conditions. The down-regulation of CB2R activity is an important marker of inflammation and and CB2R modulators have been shown to have anti-inflammatory effects. This study explored the relationship between CB2R and inflammatory responses, delved into its regulatory mechanisms in inflammatory diseases, and summarized the research progress on CB2R modulators from plants other than cannabis, including plant extracts and monomeric compounds, in exerting anti-inflammatory effects. The aim is to provide new insights into the prevention and treatment of inflammatory diseases.

Orally Administrated Inflamed Colon-Targeted Nanotherapeutics for Inflammatory Bowel Disease Treatment by Oxidative Stress Level Modulation in Colitis.

Inflammatory bowel disease (IBD) is characterized by an inappropriate and persistent inflammatory immune response and is often accompanied by excessive reactive oxygen species (ROS) production. For effective IBD treatment, there is a high demand for safe and targeted therapy that can be orally administered. In this study, we aimed to propose the use of inflamed colon-targeted antioxidant nanotherapeutics (ICANs) for in situ oxidative stress level modulation in colitis. ICANs consist of mesoporous silica nanoparticles (MSNs) with surface-attached ROS-scavenging ceria nanoparticles (CeNPs), which are further coated with poly(acrylic acid) (PAA) to facilitate preferential adherence to inflamed colon tissues through electrostatic interaction. We achieved a high ROS-scavenging property that remained effective even after artificial gastrointestinal fluid incubation by optimization of the molecular weight and PAA-coating pH. The orally administered ICANs demonstrated enhanced adherence to inflamed colon tissues in an acute inflammation mouse model of IBD induced by dextran sulfate sodium. This targeted delivery resulted in gut microenvironment modulation by regulating redox balance and reducing inflammatory cell infiltration, thereby suppressing the colitis-associated immune response. These findings highlight the potential of noninvasive ICANs as a promising candidate for treating inflammatory intestinal diseases by oxidative stress level modulation in colitis.

Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC).

A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems, and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce. In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests, and physical examination were obtained from all patients. SARS-CoV-2 reactive T-cell response was analyzed via multiparametric flow cytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay. The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache, and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells. Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

DAMPs and alarmin gene expression patterns in aging healthy and diseased mucosal tissues.

Periodontitis is delineated by a dysbiotic microbiome at sites of lesions accompanied by a dysregulated persistent inflammatory response that undermines the integrity of the periodontium. The interplay of the altered microbial ecology and warning signals from host cells would be a critical feature for maintaining or re-establishing homeostasis in these tissues. This study used a nonhuman primate model (Macaca mulatta) with naturally-occurring periodontitis (n = 34) and experimental ligature-induced periodontitis (n = 36) to describe the features of gene expression for an array of damage-associate molecular patterns (DAMPs) or alarmins within the gingival tissues. The animals were age stratified into: ≤3 years (Young), 7-12 years (Adolescent), 12-15 years (Adult) and 17-23 years (Aged). Gingival tissue biopsies were examined via microarray. The analysis focused on 51 genes representative of the DAMPs/alarmins family of host cell warning factors and 18 genes associated with tissue destructive processed in the gingival tissues. Bacterial plaque samples were collected by curette sampling and 16S rRNA gene sequences used to describe the oral microbiome. A subset of DAMPs/alarmins were expressed in healthy and naturally-occurring periodontitis tissues in the animals and suggested local effects on gingival tissues leading to altered levels of DAMPs/alarmins related to age and disease. Significant differences from adult healthy levels were most frequently observed in the young and adolescent animals with few representatives in this gene array altered in the healthy aged gingival tissues. Of the 51 target genes, only approximately ⅓ were altered by ≥1.5-fold in any of the age groups of animals during disease, with those increases observed during disease initiation. Distinctive positive and negative correlations were noted with the DAMP/alarmin gene levels and comparative expression changes of tissue destructive molecules during disease across the age groups. Finally, specific correlations of DAMP/alarmin genes and relative abundance of particular microbes were observed in health and resolution samples in younger animals, while increased correlations during disease in the older groups were noted. Thus, using this human-like preclinical model of induced periodontitis, we demonstrated the dynamics of the activation of the DAMP/alarmin warning system in the gingival tissues that showed some specific differences based on age.

Nonsevere Burn Induces a Prolonged Systemic Metabolic Phenotype Indicative of a Persistent Inflammatory Response Postinjury

Nonsevere Burn Induces a Prolonged Systemic Metabolic Phenotype Indicative of a Persistent Inflammatory Response Postinjury