Hyperinflammatory Response Research Articles

The JAK1/2 inhibitor ruxolitinib in patients with COVID-19 triggered hyperinflammation: the RuxCoFlam trial.

Dysregulated hyperinflammatory response is key in thepathogenesis in patients with severe COVID-19 leading to acute respiratory distress syndrome and multiorgan failure. Whilst immunosuppression has been proven to be effective, potential biological targets and optimal timing of treatment are still conflicting. We sought to evaluate efficacy and safety of the Janus Kinase 1/2 inhibitor ruxolitinib, employing the previously developed COVID-19 Inflammation Score (CIS) in a prospective multicenter open label phase II trial (NCT04338958). Primary objective was reversal of hyperinflammation (CIS reduction of ≥25% at day 7 in ≥20% of patients). In 184 patients with a CIS of ≥10 (median 12) ruxolitinib was commenced at an initial dose of 10 mg twice daily and applied over a median of 14 days (range, 2-31). On day 7, median CIS declined to 6 (range, 1-13); 71% of patients (CI 64-77%) achieved a ≥25% CIS reduction accompanied by a reduction of markers of inflammation. Median cumulative dose was 272.5 mg/d. Treatment was well tolerated without any grade 3-5 adverse events related to ruxolitinib. Forty-four patients (23.9%) died, all without reported association to study drug. In conclusion, ruxolitinib proved to be safe and effective in a cohort of COVID-19 patients with defined hyperinflammation.

Tuberculosis and COVID-19 Dually Affect Human Th17 Cell Immune Response.

We analyzed the features of immune response in tuberculosis and COVID-19 patients. For this, we analyzed publications released from December 2019 to March 2023; those which were published in accessible international databases ("Medline", "PubMed", "Scopus") and with keywords such as "COVID-19", "SARS-CoV-2", "tuberculosis", "pulmonary tuberculosis", "latent tuberculosis infection", "Treg", "follicular Treg", and "Treg subsets", we considered. Through our analysis, we found that tuberculosis patients who had been infected with COVID-19 previously and elevated Th1 and Th2 cell levels. High levels of Th1 and Th2 cells may serve as a positive marker, characterizing activated immune response during TB infection. COVID-19 or post-COVID-19 subjects showed decreased Th17 levels, indicating a lack of tuberculosis development. Moreover, the typical course of tuberculosis is associated with an increase in Treg level, but COVID-19 contributes to a hyperinflammatory response. According to the data obtained, the course of tuberculosis proceeds in a dissimilar way due to the distinct immune response, elicited by SARS-CoV-2. Importantly, the development of active tuberculosis with a severe course is associated with a decline in Treg levels. Both pathogens lead to disturbed immune responses, increasing the risk of developing severe TB. The insights and findings of this paper may be used to improve the future management of individuals with latent and active tuberculosis.

Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity

BackgroundThe excessive inflammatory responses provoked by SARS-CoV-2 infection are critical factors affecting the severity and mortality of COVID-19. Previous work found that two adjacent co-occurring mutations R203K and G204R (KR) on the nucleocapsid (N) protein correlate with increased disease severity in COVID-19 patients. However, links with the host immune response remain unclear.MethodsHere, we grouped nasopharyngeal swab samples of COVID-19 patients into two cohorts based on the presence and absence of SARS-CoV-2 nucleocapsid KR mutations. We performed nasopharyngeal transcriptome analysis of age, gender, and ethnicity-matched COVID-19 patients infected with either SARS-CoV-2 with KR mutations in the N protein (KR patients n = 39) or with the wild-type N protein (RG patients n = 39) and compared to healthy controls (n = 34). The impact of KR mutation on immune response was further characterized experimentally by transcriptomic and proteomic profiling of virus-like-particle (VLP) incubated cells.ResultsWe observed markedly elevated expression of proinflammatory cytokines, chemokines, and interferon-stimulated (ISGs) genes in the KR patients compared to RG patients. Using nasopharyngeal transcriptome data, we found significantly higher levels of neutrophils and neutrophil-to-lymphocyte (NLR) ratio in KR patients than in the RG patients. Furthermore, transcriptomic and proteomic profiling of VLP incubated cells confirmed a similar hyper-inflammatory response mediated by the KR variant.ConclusionsOur data demonstrate an unforeseen connection between nucleocapsid KR mutations and augmented inflammatory immune response in severe COVID-19 patients. These findings provide insights into how mutations in SARS-CoV-2 modulate host immune output and pathogenesis and may contribute to more efficient therapeutics and vaccine development.

Persistent Proclivity to a Proinflammatory State in a Human Enteroid Model of Necrotizing Enterocolitis.

Background: Necrotizing enterocolitis (NEC) is a devastating disease of premature neonates with substantial morbidity and mortality. Necrotizing enterocolitis is associated with prematurity, a hyperinflammatory response, and dysregulation of intestinal barrier function. We hypothesize that patients with NEC will have an increased hyperinflammatory intestinal response compared with those without NEC. Patients and Methods: Enteroids were generated from intestinal tissue from neonates undergoing resection. They were treated with 100 mcg/mL lipopolysaccharide (LPS), subjected to 24 hours of hypoxia inducing experimental NEC, then compared with untreated controls. Expression of tumor necrosis factor (TNF-α) and interleukin 8 (IL-8) were evaluated via reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure inflammatory response. Analysis of variance (ANOVA) determined statistical significance (p < 0.05). Results: Treated NEC-derived enteroids expressed significantly higher levels of IL-8 (RT-qPCR, p = 0.003; ELISA, p = 0.0002) compared with untreated NEC-derived enteroids with an increase in inflammatory marker concentration in those with a greater degree of prematurity (ELISA, p = 0.0015). A higher level of IL-8 was seen in NEC-derived enteroids compared with control after treatment (RT-qPCR, p = 0.024). Tumor necrosis factor-α levels were elevated in treated NEC-derived enteroids compared with untreated NEC-derived enteroids (RT-qPCR, p = 0.006; ELISA, p = 0.002) and compared with treated non-NEC-derived enteroids (RT-qPCR, p = 0.025; ELISA, p < 0.0001). Conclusions: Enteroids generated from neonates with NEC have an elevated hyperinflammatory response in response to NEC-inducing stimuli compared with controls. Enteroids generated from neonates with NEC with a greater degree of prematurity have a larger increase in inflammatory markers. This tendency toward a hyperinflammatory state may be correlated with an infant's proclivity to develop NEC and further demonstrates the hyperinflammatory state of prematurity.

Antigens from the Helminth Fasciola hepatica Exert Antiviral Effects against SARS-CoV-2 In Vitro.

SARS-CoV-2, the causal agent of COVID-19, is a new coronavirus that has rapidly spread worldwide and significantly impacted human health by causing a severe acute respiratory syndrome boosted by a pulmonary hyperinflammatory response. Previous data from our lab showed that the newly excysted juveniles of the helminth parasite Fasciola hepatica (FhNEJ) modulate molecular routes within host cells related to vesicle-mediated transport and components of the innate immune response, which could potentially be relevant during viral infections. Therefore, the aim of the present study was to determine whether FhNEJ-derived molecules influence SARS-CoV-2 infection efficiency in Vero cells. Pre-treatment of Vero cells with a tegument-enriched antigenic extract of FhNEJ (FhNEJ-TEG) significantly reduced infection by both vesicular stomatitis virus particles pseudotyped with the SARS-CoV-2 Spike protein (VSV-S2) and live SARS-CoV-2. Pre-treatment of the virus itself with FhNEJ-TEG prior to infection also resulted in reduced infection efficiency similar to that obtained by remdesivir pre-treatment. Remarkably, treatment of Vero cells with FhNEJ-TEG after VSV-S2 entry also resulted in reduced infection efficiency, suggesting that FhNEJ-TEG may also affect post-entry steps of the VSV replication cycle. Altogether, our results could potentially encourage the production of FhNEJ-derived molecules in a safe, synthetic format for their application as therapeutic agents against SARS-CoV-2 and other related respiratory viruses.

Difficulties of differential diagnosis of multisystem inflammatory syndrome associated with SARS-CoV-2 in a teenager (clinical case)

The new coronavirus infection does not lose its relevance, which is due to the ubiquity of the virus, the variety of strains, clinical manifestations and their consequences of COVID-19. In children, one of the severe complications of new coronavirus infection is the multisystem inflammatory syndrome associated with SARS-CoV-2 (MIS-C), which is characterized by a hyperinflammatory response with damage to two or more organs and systems. MIS-C requires differential diagnosis with other diseases with similar symptoms: bacterial infections, sepsis, toxic shock syndrome, Kawasaki syndrome, hemophagocytic syndrome. As an example, the article considers a clinical case of MIS-C in a 13-year-old girl 4 weeks after undergoing new coronavirus infection (confirmed). At the onset of the disease, the leading manifestations were systemic inflammatory response syndrome (fever, increased markers of inflammation) with damage to the cardiovascular system, skin and mucous membranes, lymphadenitis, thrombocytopenia. According to the severity of the condition, the child required observation and treatment in the intensive care unit. The absence of the expected effect of the recommended MIS-C therapy (intravenous immunoglobulin and pulse therapy with methylprednisolone) on the first day did not allow to exclude bacterial infection complicated by sepsis in the above clinical situation, therefore, it was suggested that the combined course of MIS-C and bacterial infection of unspecified etiology, which probably led to a more severe course of the disease. In the outcome of the MIS-C the child had the formation of a long-term depressive state (diagnosed by a psychiatrist), for which the patient received drug therapy and psychological assistance.&#x0D; The described case showed difficulties in the formulation of the final diagnosis due to the presence in the patient of several symptoms and syndromes characteristic of various diseases, the absence of an identified etiological agent and the absence of the expected positive effect with standard therapy of the disease. In addition, a pathology was revealed in the catamnesis, which required dynamic observation of the child by several specialized specialists.

Effectiveness of corticosteroids in the treatment of patients with Covid 19

The COVID-19 pandemic caused by the SARS-CoV-2 virus has emerged as one of the most significant health crises of the 21st century, with a devastating impact on global health. Understanding the disease pathogenesis and finding effective treatment strategies are crucial to mitigate its mortality rate. COVID-19 exhibits a biphasic illness, characterized by a viral response phase followed by a hyperinflammatory response phase, also known as the cytokine storm. This cytokine storm, rather than direct viral activity, has been identified as the major contributor to the high mortality associated with severe cases.&#x0D; In this article, we explore the effectiveness of corticosteroids in managing the cytokine storm and reducing mortality in COVID-19. Corticosteroids have been extensively studied for their immunosuppressive properties and have shown potential in suppressing the hyperinflammatory response associated with the disease. The RECOVERY trial, a large-scale multicenter clinical trial conducted in the UK, demonstrated a significant reduction in mortality with the use of corticosteroids, particularly in critically ill patients requiring invasive mechanical ventilation.&#x0D; However, the timing of corticosteroid therapy initiation is crucial, as early administration or use in milder cases may not yield the same benefits and could potentially increase mortality. Current evidence suggests that corticosteroids should be reserved for hospitalized patients with severe COVID-19, specifically those requiring oxygen therapy or invasive mechanical ventilation. In contrast, corticosteroid therapy has shown limited or even detrimental effects in non-severe cases.

Deacetyl epoxyazadiradione ameliorates BPA-induced neurotoxicity by mitigating ROS and inflammatory markers in N9 cells and zebrafish larvae

Bisphenol A (BPA) leaches from plastic products have become a major inevitable concern among the research society. Human exposure to BPA leads to deleterious effects on multiple organs by the induced hyper inflammatory and oxidative stress responses. Due to the compromised antioxidant mechanism, the brain environment was highly susceptible and required special concern to ameliorate the effects of BPA. Hence, this study investigates the potential of neem-derived semi natural deacetyl epoxyazadiradione (DEA) against the oxidative stress and inflammatory response induced by BPA exposure in N9 cells and zebrafish larvae. The results from the in vitro analyses showed a decrease in cell viability in the MTT assay and a decline in mitochondrial damage in BPA-exposed N9 cells. Further in vivo, results revealed that pre-treatment of DEA to zebrafish larvae has significantly reduced the level of superoxide anion and increased the production of antioxidant enzymes such as SOD, CAT, GST, GPx and GR. We also found a significant decrease in the production of nitric oxide (p < 0.0001) and iNOS gene expression at 150 μM concentration. Further, DEA pre-treatment improved the behaviour of zebrafish larvae by ameliorating the production of the AChE enzyme. In conclusion, DEA protected zebrafish larvae from BPA toxicity by ameliorating oxidative stress and inflammatory responses.

Coevolution of furA-Regulated Hyper-Inflammation and Mycobacterial Resistance to Oxidative Killing through Adaptation to Hydrogen Peroxide.

Mycobacterium tuberculosis (Mtb) is highly resistant to host oxidative killing. We hypothesized that the evolutionary adaptation of M. smegmatis to hydrogen peroxide (H2O2) would endow the nonpathogenic Mycobacterium persistent in a host. In the study, we screened a highly H2O2-resistant strain (mc2114) via evolutionary H2O2 adaptation in vitro. The MIC of mc2114 to H2O2 is 320 times that of wild-type mc2155. Mouse infection experiments showed that mc2114, similar to Mtb, was persistent in the lungs and caused high lethality in mice with restricted responses of NOX2, ROS, IFN-γ, decreased macrophage apoptosis, and overexpressed inflammatory cytokines in the lungs. Whole-genome sequencing analysis revealed that mc2114 harbored 29 single nucleotide polymorphisms in multiple genes; one of them was on the furA gene that caused FurA deficiency-mediated overexpression of KatG, a catalase-peroxidase to detoxify ROS. Complementation of mc2114 with a wild-type furA gene reversed lethality and hyper-inflammatory response in mice with rescued overexpression of KatG and inflammatory cytokines, whereas NOX2, ROS, IFN-γ, and macrophage apoptosis remained reduced. The results indicate that although FurA regulates KatG expression, it does not contribute significantly to the restriction of ROS response. Instead, FurA deficiency is responsible for the detrimental pulmonary inflammation that contributes to the severity of the infection, a previously nonrecognized function of FurA in mycobacterial pathogenesis. The study also indicates that mycobacterial resistance to oxidative burst results from complex mechanisms involving adaptive genetic changes in multiple genes. IMPORTANCE Mycobacterium tuberculosis (Mtb) causes human tuberculosis (TB), which has killed more people in human history than any other microorganism. However, the mechanisms underlying Mtb pathogenesis and related genes have not yet been fully elucidated, which impedes the development of effective strategies for containing and eradicating TB. In the study, we generated a mutant of M. smegmatis (mc2114) with multiple mutations by an adaptive evolutionary screen with H2O2. One of the mutations in furA caused a deficiency of FurA, which mediated severe inflammatory lung injury and higher lethality in mice by overexpression of inflammatory cytokines. Our results indicate that FurA-regulated pulmonary inflammation plays a critical role in mycobacterial pathogenesis in addition to the known downregulation of NOX2, ROS, IFN-γ responses, and macrophage apoptosis. Further analysis of the mutations in mc2114 would identify more genes related to the increased pathogenicity and help in devising new strategies for containing and eradicating TB.

Rational use of corticosteroid treatment in the early phase of severe COVID-19

Mechanisms of hypoxemia in COVID-19 pneumonia include pulmonary inflammation, alveolar collapse, atelectasis, and pulmonary intravascular coagulopathy due to a hyperinflammatory response to SARS-CoV-2 infection. Systemic corticosteroids are widely applied as a standard treatment for hospitalized COVID-19 patients after several studies have shown favorable outcomes. However, the standard dosing and tailoring of corticosteroids in COVID-19 patients have not been established. Differences in dosing and timing of corticosteroid use may affect the outcome of COVID-19 patients. Inappropriate use of corticosteroids can lead to less benefit and potentially harmful adverse events. Dexamethasone is the most widely used corticosteroid as a result of the positive outcome from the RECOVERY study and its high anti-inflammatory potency. Although several studies have shown the benefit of higher dose corticosteroids in severe COVID-19 patients, serious adverse events associated with the use of corticosteroids, such as superimposed bacterial and/or fungal infections, have also been observed. Therefore, in this article, we reviewed current evidence of corticosteroid usage in COVID-19 patients and suggested a strategy for tailoring corticosteroid usage according to the clinical severity and risk of the patients.

MIA mice exhibit enteric nerve defects and are more susceptible to dextran sulfate sodium-induced colitis

Maternal immune activation (MIA) during pregnancy impairs the development of the central nervous system as well as the peripheral nervous system. Emerging evidence indicates that individuals with MIA suffer more from gastrointestinal disorders. The present study aims to test the hypothesis that MIA-induced susceptibility to inflammatory bowel disease is due to defects in the innervation of mucosal sensory nerves. Acute dextran sulfate sodium (DSS) colitis was induced in MIA and control adult mice. Body weight loss, disease activity index and colonic histological changes were measured during colitis. The study found that MIA mice were hypersusceptible to DSS-induced colitis and that macrophage infiltration and cytokine production were elevated in the colon of MIA mice. In vitro experiments also demonstrated that colonic macrophages from MIA mice presented hyperinflammatory responses to LPS stimulation. Sensory nerve-secreted calcitonin gene–related peptide (CGRP) is an important neuropeptide in modulating enteric inflammation. Intriguingly, we found that CGRP-positive nerves were sparsely distributed in the colon of MIA mice regardless of DSS treatment. And the protein level of CGRP was significantly reduced in colon of MIA mice. However, there was no decrease in the number of CGRP-positive cell bodies in either the DRG or vagal ganglion, suggesting that innervation defects of CGRP mucosal sensory nerves exist in the colon of MIA mice. Critically, administration of recombinant CGRP to MIA mice during DSS colitis significantly reversed their hyperinflammatory pathology. Additionally, the hyperinflammatory phenotype of colonic macrophages of MIA mice could also be reversed by CGRP treatment in vitro. Collectively, these findings suggested that the sensor nerve innervation defect-induced CGRP deficiency in MIA mice participates in their increased susceptibility to colitis. Thus, sensor nerve-secreted CGRP may be a new therapeutic target for autism combined with inflammatory bowel disease.

Inflammasomes during SARS-CoV-2 infection and development of their corresponding inhibitors.

Corona Virus Disease 2019 (COVID-19) continues to be a burden for human health since its outbreak in Wuhan, China in December 2019. Recently, the emergence of new variants of concerns (VOCs) is challenging for vaccines and drugs efficiency. In severe cases, SARS-CoV-2 provokes inappropriate hyperinflammatory immune responses leading to acute respiratory distress syndrome (ARDS) and even death. This process is regulated by inflammasomes which are activated after binding of the viral spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2) receptor and triggers innate immune responses. Therefore, the formation of "cytokines storm" leads to tissue damage and organ failure. NOD-like receptor family pyrin domain containing 3 (NLRP3) is the best studied inflammasome known to be activated during SARS-CoV-2 infection. However, some studies suggest that SARS-CoV-2 infection is associated with other inflammasomes as well; such as NLRP1, absent in melanoma-2 (AIM-2), caspase-4 and -8 which were mostly found during dsRNA virus or bacteria infection. Multiple inflammasome inhibitors that exist for other non-infectious diseases have the potential to be used to treat severe SARS-CoV-2 complications. Some of them have showed quite encouraging results during pre- and clinical trials. Nevertheless, further studies are in need for the understanding and targeting of SARS-Cov-2-induced inflammasomes; mostly an update of its role during the new VOCs infection is necessary. Hence, this review highlights all reported inflammasomes involved in SARS-CoV-2 infection and their potential inhibitors including NLRP3- and Gasdermin D (GSDMD)-inhibitors. Further strategies such as immunomodulators and siRNA are also discussed. As highly related to COVID-19 severe cases, developing inflammasome inhibitors holds a promise to treat severe COVID-19 syndrome effectively and reduce mortality.

Metabolic reprogramming through mitochondrial biogenesis drives adenosine anti-inflammatory effects: new mechanism controlling gingival fibroblast hyper-inflammatory state.

Fibroblasts are the dominant stromal cells in the gingival lamina propria with a well-established relevance in regulation of inflammation, and in innate immunity. This is exemplified by their hypersecretion of CXCL8, enhancing leukocyte infiltration in chronic and sustained inflammatory conditions. We have previously shown adenosine to be a key metabolic nucleoside that regulates stromal inflammation, but the underlying mechanisms linking adenosine to the metabolic status of fibroblasts and to the resultant inflammatory response are unclear. This study examined, by seahorse real-time cell metabolic analysis, the bioenergetics of the stromal fibroblast response to extracellular adenosine and IL-1β, focusing on CXCL8 secretion by primary human gingival fibroblasts (HGF). Markers of the glycolytic pathway and mitochondrial biogenesis were tracked through immunoblot. Further, the influence of adenosine on mitochondrial accumulation was measured by uptake of MitoTracker Red fluorescent probe and assessment of the role of FCCP (a mitochondrial uncoupler) in CXCL8 secretion and mitochondrial accumulation. Our results show that the anti-inflammatory response of HGF to extracellular adenosine, typified by reduced CXCL8 secretion, is mediated by mitochondrial oxidative phosphorylation, reflected in higher oxygen consumption rate (OCR). In the presence of IL-1β, adenosine-treated cells induced higher ATP production, basal respiration and proton leak compared to IL-1β without adenosine. Surprisingly, adenosine had no additional effect on the IL-1β-induced higher glycolysis rate demonstrated by the extracellular acidification rate (ECAR). In addition, the higher OCR in adenosine-stimulated cells was not due to the mitochondrial fuel dependency or capacity, but due to an increase in mitochondrial biogenesis and accumulation in the cells with concomitant decrease in mitophagy-required p-PINK1 marker. We detected the accumulation of functional mitochondria with increased activation of the AMPK/SIRT1/PGC-1α pathway. The adenosine-induced uptake of MitoTracker was abrogated by PGC-1α inhibition with SR-12898. In addition, the adenosine effects on reduced CXCL8 were ablated by treatment with FCCP, a potent uncoupler of mitochondrial oxidative phosphorylation. Our findings reveal a key role for mitochondrial bioenergetics in regulation of CXCL8-mediated inflammation by HGF through the adenosine/AMPK/SIRT1/PGC-1α axis. Therapeutically targeting this pathway in gingival fibroblasts might be a promising future strategy to modulate stromal-mediated sustained hyper-inflammatory responses.

Therapeutic prospects of naturally occurring p38 MAPK inhibitors tanshinone IIA and pinocembrin for the treatment of SARS-CoV-2-induced CNS complications.

P38 mitogen-activated protein kinase (p38 MAPK) signaling pathway is closely related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replication and hyperinflammatory responses in coronavirus disease 2019 (COVID-19). Therefore, blood-brain barrier-penetrating p38 MAPK inhibitors have good potential for the treatment of central nervous system (CNS) complications of COVID-19. The aim of the present study is the characterization of the therapeutic potential of tanshinone IIA and pinocembrin for the treatment of CNS complications of COVID-19. Studies published in high-quality journals indexed in databases Scopus, Web of Science, PubMed, and so forth were used to review the therapeutic capabilities of selected compounds. In continuation of our previous efforts to identify agents with favorable activity/toxicity profiles for the treatment of COVID-19, tanshinone IIA and pinocembrin were identified with a high ability to penetrate the CNS. Considering the nature of the study, no specific time frame was determined for the selection of studies, but the focus was strongly on studies published after the emergence of COVID-19. By describing the association of COVID-19-induced CNS disorders with p38 MAPK pathway disruption, this study concludes that tanshinone IIA and pinocembrin have great potential for better treatment of these complications. The inclusion of these compounds in the drug regimen of COVID-19 patients requires confirmation of their effectiveness through the conduction of high-quality clinical trials.

Bugs and the barrier: A review of the gut microbiome and intestinal barrier in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease that affects premature neonates. It frequently results in significant morbidity and mortality for those affected. Years of research into the pathophysiology of NEC have revealed it to be a variable and multifactorial disease. However, there are risk factors associated with NEC including low birth weight, prematurity, intestinal immaturity, alterations in microbial colonization, and history of rapid or formula based enteral feeds (Fig. 1).1–3 An accepted generalization of the pathogenesis of NEC includes a hyperresponsive immune reaction to insults such as ischemia, starting formula feeds, or alterations in the microbiome with pathologic bacterial colonization and translocation. This reaction causes a hyperinflammatory response disrupting the normal intestinal barrier, allowing abnormal bacterial translocation and ultimately sepsis.1,2,4 This review will focus specifically on the interactions with the microbiome and intestinal barrier function in NEC.

ID: 212135 Noninvasive Human Immunotyping Through Machine Learning Using the Autonomic Nervous System

The extreme diversity of the human immune system, forged and maintained throughout evolutionary history, has to date provided a potent defense against pathogens [1]. Intrinsically variable autonomic neuro-immune regulation via β-adrenergic receptor and α7-nicotinic acetylcholine receptor activity is controlled by polymorphic genes and environmental sensors [2, 3]. While most healthy humans have the capacity to activate various types of immune cells, interferons, inflammasome activity, and vagal anti-inflammatory reflexes, individuals differ in the degree to which they are primed for each functional configuration. Virulent emerging pathogens inherently circumvent these functional immune configurations and can impose a dysregulated hyperinflammatory response [4]. Here we detect host-dependent baseline autonomic gradient drive (AGD) bias through high temporal resolution physiological monitoring. Similar to immune bias, AGD bias shown to predict current inflammatory status as well as severity of future inflammatory sequela and disease.

Emerging Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome Associated With COVID-19 in Children.

Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare delayed hyperinflammatory response to SARS-CoV-2 infection and causes severe morbidity in the pediatric age group. Although MIS-C shares many clinical similarities to Kawasaki disease (KD), important differences in epidemiologic, clinical, immunologic, and potentially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemiologic features include male predominance, peak age of 6 to12 years, and specific racial or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and neurologic complaints, and patients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnormalities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein-as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens-are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that underlie the pathogenesis of MIS-C vs both acute SARS-CoV-2 infection and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine-associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac complications, provide insights into the underlying immunologic pathophysiology, and define similarities and differences with KD.

Biofilm-forming strains of P. aeruginosa and S. aureus isolated from cystic fibrosis patients differently affect inflammatory phenotype of macrophages

ObjectiveLung cystic fibrosis (CF) is characterized by chronic infections and hyperinflammatory response of neutrophils and macrophages. P. aeruginosa (PA) and S. aureus (MSSA, MRSA) are major pathogens of advanced CF. The main goal of this study was to compare the inflammatory phenotype of murine C57BL/6 macrophages exposed to PA57 with that exposed to MSSA60, both strains isolated from the same patient with severe CF. In the present study, we used C57BL/6 mice sensitive to lung infection with P. aeruginosa.MethodsWe measured the release of cytokines and the expression of phenotypic markers of murine neutrophils and macrophages exposed to bacterial cells and biofilm components (i.e., EPS) of the selected bacteria. In addition, a quantitative proteomic approach was used for the characterization of proteome-wide changes in macrophages.ResultsNeutrophils stimulated with PA57 and MSSA60 strains produced hyperinflammatory pattern of cytokines. The pro-inflammatory impact of PA57 was significantly higher than that of MSSA60 (IL-6/IL-10 ratio: PA57 = 9.3 vs. MSSA60 = 1.7). Macrophages produced significantly lower amount of cytokines, but showed classical pattern of M1 markers (iNOS-High; arginase-1 and mannose receptor MRC1-Low). Importantly, as evidenced by proteomic analysis, PA57 and PA57-EPS were stronger inducers of M1 macrophage polarization than the MSSA60 counterparts.ConclusionsOur study demonstrated that strong biofilm P. aeruginosa strains, CF isolates, are dominant inducers of M1 macrophages, termed biofilm-associated macrophages (BAMs). We suggest that repolarization of detrimental BAMs might be a new therapeutic strategy to ameliorate the airway damage in CF.

Hand infection: a management approach based on a new understanding of combined bacterial and neutrophil mediated tissue damage.

Concepts of tissue damage from sepsis are rooted in the works of Pasteur regarding colonization by microorganisms, and Lister's observation of avoiding suppuration by their exclusion. The reactive inflammation has been considered a beneficial defence mechanism. A more complex biology is now unfolding of pathogenic mechanisms with toxins produced by the organisms now being placed in a broad category of virulence factors. Neutrophils are key cells in providing innate immunity and their trafficking to sites of infection results in entry to the extracellular space where they attack pathogens by release of the contents of neutrophil granules and neutrophil extracellular traps. There is now considerable evidence that much of the tissue damage in infection is due to excessive host innate immunological reaction; a hyperinflammatory response, whether localized or systemic. In addition to traditional surgical methods of drainage and decompression there is now a focus on dilution of inflammatory mediators. This emerging knowledge can potentially alter the way we approach hand infections.

Serum IL-23, IL-10, and TNF-α predict in-hospital mortality in COVID-19 patients.

The hyperinflammatory response, caused by severe acute respiratory syndrome-2 (SARS-CoV-2), is the most common cause of death in patients with coronavirus disease 2019 (COVID-19). The etiopathogenesis of this illness is not fully understood. Macrophages appear to play a key part in COVID-19's pathogenic effects. Therefore, this study aims to examine serum inflammatory cytokines associated with the activation state of macrophages in COVID-19 patients and attempt to find accurate predictive markers for disease severity and mortality risk in hospital. 180 patients with COVID-19 and 90 healthy controls (HCs) participated in this study. Patients were divided into three different subgroups, mild (n=81), severe (n=60), and critical groups (n=39). Serum samples were collected and IL (Interleukin)-10, IL-23, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1) and chemokine ligand 3 (CCL3) were determined by ELISA. In parallel, myeloperoxidase (MPO) and C-reactive protein (CRP) were measured using colorimetric and electrochemiluminescence methods, respectively. Data were collected, and their associations with disease progression and mortality were assessed using regression models and receiver operating characteristic (ROC) curves. Compared to HCs, a significant increase in IL-23, IL-10, TNF-α, IFN-γ and MCP-1, were observed in COVID-19 patients. Serum levels of IL-23, IL-10, and TNF-α were significantly higher in COVID-19 patients with critical cases compared to mild and severe cases, and correlated positively with CRP level. However, non-significant changes were found in serum MPO and CCL3 among the studied groups. Moreover, significant positive association has been observed among increased IL-10, IL-23 and TNF-α in serum of COVID-19 patients. Furthermore, a binary logistic regression model was applied to predict death's independent factors. Results showed that IL-10 alone or in combination with IL23 and TNF-α are strongly linked with non-survivors in COVID-19 patients. Finally, ROC curve results uncovered that IL-10, IL-23 and TNF-α were excellent predictors for prognosing COVID-19. The elevations of IL-10, IL-23, and TNF-α levels were seen in severe and critical cases of COVID-19 patients and their elevations were linked to the in-hospital mortality of the disease. A prediction model shows that the determination of these cytokines upon admission is important and should be done on COVID-19 patients as a way of evaluating the prognosis of the disease. COVID-19 Patients with high IL-10, IL-23, and TNF-α on admission are more likely to experience a severe form of the disease; therefore, those patients should be cautionary monitored and treated.