Systemic inflammatory Th1 cytokines during Trypanosoma cruzi infection disrupt the typical anatomical cell distribution and phenotypic/functional characteristics of various cell subsets within the thymus.

The thymus plays a crucial role in T cell differentiation, a complex process influenced by various factors such as antigens, the microenvironment and thymic architecture. The way the thymus resolves infections is critical, as chronic persistence of microbes or inflammatory mediators can obstruct the differentiation. Here, we illustrate that following inflammatory T helper 1 infectious processes like those caused by Candida albicans or Trypanosoma cruzi, single positive thymocytes adopt a mature phenotype. Further investigations focused on T. cruzi infection, reveal a substantial existence of CD44+ cells in both the cortical and medullary areas of the thymus at the onset of infection. This disturbance coincides with heightened interferon gamma (IFNγ) production by thymocytes and an increased cytotoxic capacity against T. cruzi-infected macrophages. Additionally, we observe a reduced exportation capacity in T. cruzi-infected mice. Some alterations can be reversed in IFNγ knockout mice (KO). Notably, the majority of these effects can be replicated by systemic expression of interleukin (IL)-12+IL-18, underlining the predominantly inflammatory rather than pathogen-specific nature of these phenomena. Understanding the mechanisms through which systemic inflammation disrupts normal T cell development, as well as subsequent T cell exportation to secondary lymphoid organs (SLO) is pivotal for comprehending susceptibility to diseases in different pathological scenarios.

Protective effects of IL18-105G > A and IL18-137C > Ggenetic variants on severity of COVID-19.

OBJECTIVE AND DESIGN: A cross-sectional study evaluated the IL18-105G > A (rs360717) and IL18-137C > G (rs187238) variants on Coronavírus Disease 2019 (COVID-19) severity. SUBJECTS AND METHODS: 528 patients with COVID-19 classifed with mild (n = 157), moderate (n = 63) and critical (n = 308) disease were genotpyed for the IL18-105G > A and IL18-137C > G variants. RESULTS: We observed associations between severe + critical COVID-19 groups (reference group was mild COVID-19) and the IL18-105G > A (p = 0.008) and IL18-137C > G (p = 0.01) variants, which remained significant after adjusting for sex, ethnicity and age. Consequently, we have examined the associations between moderate + critical COVID-19 and the genotypes of both variants using different genetic models. The IL18-105G > A was associated with severe disease (moderate + critical), with effects of the GA genotype in the codominant [Odds ratio (OR), (95 % confidence interval) 0.55, 0.34-0.89, p = 0.015], overdominant (0.56, 0.35-0.89, p = 0.014) and dominant (0.60, 0.38-0.96, p = 0.031) models. IL18-105 GA coupled with age, chest computed tomograhy scan anormalities, body mass index, heart diseases, type 2 diabetes mellitus, hypertension, and inflammation may be used to predict the patients who develop severe disease with an accuracy of 84.3 % (sensitivity: 83.3 % and specificity: 86.5 %). Therefore, the presence of the IL18-105 A allele in homozygosis or heterozygosis conferred about 44.0 % of protection in the development of moderate and severe COVID-19. The IL18-137C > G variant was also associated with protective effects in the codominant (0.55, 0.34-0.89, p = 0.015), overdominant (0.57, 0.36-0.91, p = 0.018), and dominant models (0.59, 0.37-0.93, p = 0.025). Therefore, the IL18-137 G allele showed a protective effect against COVID-19 severity. CONCLUSION: The IL18-105G > A and IL18-137C > Gvariants may contribute with protective effects for COVID-19 severity and the effects of IL18-137C > G may be modulating IL-18 production and Th1-mediated immune responses.

Co-Formulation of Recombinant Porcine IL-18 Enhances the Onset of Immune Response in a New Lawsonia intracellularis Vaccine.

Pig is one of the most consumed meats worldwide. One of the main conditions for pig production is Porcine Enteropathy caused by Lawsonia intracellularis. Among the effects of this disease is chronic mild diarrhea, which affects the weight gain of pigs, generating economic losses. Vaccines available to prevent this condition do not have the desired effect, but this limitation can be overcome using adjuvants. Pro-inflammatory cytokines, such as interleukin 18 (IL-18), can improve an immune response, reducing the immune window of protection. In this study, recombinant porcine IL-18 was produced and expressed in Escherichia coli and Pichia pastoris. The protein's biological activity was assessed in vitro and in vivo, and we determined that the P. pastoris protein had better immunostimulatory activity. A vaccine candidate against L. intracellularis, formulated with and without IL-18, was used to determine the pigs' cellular and humoral immune responses. Animals injected with the candidate vaccine co-formulated with IL-18 showed a significant increase of Th1 immune response markers and an earlier increase of antibodies than those vaccinated without the cytokine. This suggests that IL-18 acts as an immunostimulant and vaccine adjuvant to boost the immune response against the antigens, reducing the therapeutic window of recombinant protein-based vaccines.

High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1ß and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.

Noncanonical NLRP3 Inflammasome Activation: Standard Protocols.

The canonical activation of multimeric inflammasomes usually occurs through caspase-1 activation, and it is characterized by the presence of extracellular IL-1ß and IL-18 or measuring danger signal proteins, such as HMGB1 using enzyme-linked immunosorbent assay (ELISA) or Western blots; these assays differentiate non-cleaved and cleaved forms of these two cytokines (the cleaved form is the mature and active form). Similar techniques can be used to assess noncanonical inflammasome activation. Real-time PCR can measure the relative mRNA expression for a specific gene, whereas Western blots or immunocytochemistry can detect the presence of proteins by binding of specific antibodies to their antigens in biological samples. Moreover, noncanonical inflammasome activation can be evaluated through the cleavage of the amino and the carboxy terminals of one important component, gasdermin D (GSDMD), whose cleavage induces its pyroptotic activity. Thus, the analysis of cleaved GSDMD is an ideal pathway to study the noncanonical inflammasome. ELISA and immunoblot can be performed on cell culture supernatants or cell extracts.

Peonidin-3-O-glucoside and Resveratrol Increase the Viability of Cultured Human hFOB Osteoblasts and Alter the Expression of Genes Associated with Apoptosis, Osteoblast Differentiation and Osteoclastogenesis.

High-throughput RNA-sequencing can determine the impact of nutrients and their combinations on gene transcription levels in osteocytes, and clarify the biological pathways associated with their impact on bone tissues. Previously, we reported that resveratrol (RES) and peonidin-3-O-glucoside (POG) increased osteoblastogenesis, as well as reduced osteoclastogenesis in transgenic teleost fish models. Here, we perform whole-genome transcriptomic profiling of osteoblasts treated with POG or RES to provide a comprehensive understanding of alterations in gene expression and the molecular mechanisms involved. Cultured human fetal osteoblastic hFOB 1.19 cells were treated with the test compounds, and then RNA was used to prepare RNA-seq libraries, that were sequenced using a NovaSeq 6000. Treatment with POG or RES increased osteoblast proliferation and reduced apoptosis. Transcriptomic profiling showed that of the 29,762 genes investigated, 3177 were differentially expressed (1481 upregulated, 1696 downregulated, FDR ≤ 0.05) in POG-treated osteoblasts. In the RES-treated osteoblasts, 2288 genes were differentially expressed (DGEs, 1068 upregulated, 1220 downregulated, FDR ≤ 0.05). Ingenuity® Pathway Analysis (IPA) of DGEs from RES or POG-treated osteoblasts revealed significant downregulation of the apoptosis, osteoarthritis and HIF1α canonical pathways, and a significant reduction in Rankl mRNA expression. The data suggest that RES and POG have both anabolic and anticlastogenic effects.

The immunogenic involvement of miRNA-492 in mycoplasma pneumoniae infection in pediatric patients

Abstract Objective: This study aimed to evaluate the role of miRNA-492 in the progression of mycoplasma pneumoniae (MP) infection in pediatric patients. Methods: Forty-six children admitted to the present study's hospital and diagnosed with mycoplasma pneumonia were recruited as the study group from March 2018 to August 2019, and 40 healthy children were selected as the control group. Results: The expression levels of miRNA-492, TNF-α, IL-6 and IL-18 in the study group were significantly higher than those in the control group (p < 0.05). There was no significant correlation between miRNA-492 and most of the immune-correlated indicators in the study group, except for IL-6, IL-18 and HMGB1. Meanwhile, overexpression of miRNA-492 increased IL-6 secretion in PMA-activated monocytes (p < 0.01). Conclusion: The present study's results suggested that miRNA-492 might play a role in the pathogenesis of mycoplasma pneumoniae pneumonia in children by regulating the secretion of immune-inflammatory factors such as IL-6 and IL-18 in the mononuclear macrophages.

Imbalanced IL-1B and IL-18 Expression in Sézary Syndrome.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T-cell lymphoma, with an abnormal inflammatory response in affected skin. The cytokines IL-1B and IL-18, as key signaling molecules in the immune system, are produced in an inactive form and cleave to the active form by inflammasomes. In this study, we assessed the skin, serum, peripheral mononuclear blood cell (PBMC) and lymph-node samples of SS patients and control groups (healthy donors (HDs) and idiopathic erythroderma (IE) nodes) to investigate the inflammatory markers IL-1B and IL-18 at the protein and transcript expression levels, as potential markers of inflammasome activation. Our findings showed increased IL-1B and decreased IL-18 protein expression in the epidermis of SS patients; however, in the dermis layer, we detected increased IL-18 protein expression. In the lymph nodes of SS patients at advanced stages of the disease (N2/N3), we also detected an enhancement of IL-18 and a downregulation of IL-1B at the protein level. Moreover, the transcriptomic analysis of the SS and IE nodes confirmed the decreased expression of IL1B and NLRP3, whereas the pathway analysis indicated a further downregulation of IL1B-associated genes. Overall, the present findings showed compartmentalized expressions of IL-1B and IL-18 and provided the first evidence of their imbalance in patients with Sézary syndrome.

The immunogenic involvement of miRNA-492 in mycoplasma pneumoniae infection in pediatric patients.

OBJECTIVE: This study aimed to evaluate the role of miRNA-492 in the progression of mycoplasma pneumoniae (MP) infection in pediatric patients. METHODS: Forty-six children admitted to the present study's hospital and diagnosed with mycoplasma pneumonia were recruited as the study group from March 2018 to August 2019, and 40 healthy children were selected as the control group. RESULTS: The expression levels of miRNA-492, TNF-α, IL-6 and IL-18 in the study group were significantly higher than those in the control group (p < 0.05). There was no significant correlation between miRNA-492 and most of the immune-correlated indicators in the study group, except for IL-6, IL-18 and HMGB1. Meanwhile, overexpression of miRNA-492 increased IL-6 secretion in PMA-activated monocytes (p < 0.01). CONCLUSION: The present study's results suggested that miRNA-492 might play a role in the pathogenesis of mycoplasma pneumoniae pneumonia in children by regulating the secretion of immune-inflammatory factors such as IL-6 and IL-18 in the mononuclear macrophages.

Relationship between IL-17, TNF-α, IL-10, IFN-γ, and IL-18 polymorphisms with the outcome of hepatitis B virus infection in the Turkish population

SUMMARY OBJECTIVE: Hepatitis B virus is a global threat that can lead to liver cirrhosis and hepatocellular carcinoma. For the treatment of chronic hepatitis B virus, polymorphisms might be an option for gene treatments. This study aimed to investigate the effects of IL-17, TNF-α, IL-10, IFN-γ, and IL-18 gene polymorphisms on hepatitis B virus infection in the Turkish population. METHODS: The genotypes and allele distribution of 75 patients exposed to hepatitis B virus and 50 healthy control individuals were analyzed. The real-time polymerase chain reaction method was used for identification. RESULTS: A correlation was observed between susceptibility to hepatitis B virus infection and IL-17 Exon 3/3'UTR (rs1974226) C, IL-17 Exon 3 (rs763780) A, IL-18 (-607) (rs1946518) A alleles, and IL-17 Exon 3 (rs763780) AA genotype (p=0.006, p=0.009, p=0.025, and p=0.008, respectively). Furthermore, IL-18 (-137) (rs187238) TT genotype and TNF-α-308 (rs1800629) G and A alleles, were associated with protection against hepatitis B virus infection (p=0.0351 and p=0.032, respectively). CONCLUSION: This study demonstrated that TNF-α (-308), IL-17 (Exon 3/3' UTR), IL-17 (Exon 3), and IL-18 (-607) polymorphisms are associated with hepatitis B virus infection. Therefore, these may serve as potential therapeutic targets for chronic viral hepatitis in the Turkish population.

Exploring the immunomodulatory role of virtual memory CD8+ T cells: Role of IFN gamma in tumor growth control.

Virtual memory CD8+ T cells (TVM) have been described as cells with a memory-like phenotype but without previous antigen (Ag) exposure. TVM cells have the ability to respond better to innate stimuli rather than by TCR engagement, producing large amounts of interferon gamma (IFNγ) after stimulation with interleukin (IL)-12 plus IL-18. As a result of the phenotypic similarity, TVM cells have been erroneously included in the central memory T cell subset for many years. However, they can now be discriminated via the CD49d receptor, which is up-regulated only on conventional memory T cells (TMEM) and effector T cells (TEFF) after specific cognate Ag recognition by a TCR. In this work we show that systemic expression of IL-12 plus IL-18 induced an alteration in the normal TVM vs TMEM/TEFF distribution in secondary lymphoid organs and a preferential enrichment of TVM cells in the melanoma (B16) and the pancreatic ductal adenocarcinoma (KPC) tumor models. Using our KPC bearing OT-I mouse model, we observed a significant increase in CD8+ T cell infiltrating the tumor islets after IL-12+IL-18 stimulation with a lower average speed when compared to those from control mice. This finding indicates a stronger interaction of T cells with tumor cells after cytokine stimulation. These results correlate with a significant reduction in tumor size in both tumor models in IL-12+IL-18-treated OT-I mice compared to control OT-I mice. Interestingly, the absence of IFNγ completely abolished the high antitumor capacity induced by IL-12+IL-18 expression, indicating an important role for these cytokines in early tumor growth control. Thus, our studies provide significant new information that indicates an important role of TVM cells in the immune response against cancer.

Lessons from the Cerebrospinal Fluid Analysis of HTLV-1-Infected Individuals: Biomarkers of Inflammation for HAM/TSP Development.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease that leads to motor impairment due to a chronic inflammatory process in the central nervous system (CNS). However, the HAM/TSP pathogenesis is not completely clear, and biomarkers to define the disease prognosis are still necessary. Thus, we aimed to identify biomarkers for HAM/TSP and potential mechanisms involved in disease development. To that end, the concentrations of VILIP-1, BDNF, VEGF, ß-NGF, TGF-ß1, fractalkine/CX3CL1, IL-6, IL-18, and TNF-α, and the soluble forms of TREM-1, TREM-2, and RAGE, were assessed using a multiplex bead-based immunoassay in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n = 20), asymptomatic HTLV-1 carriers (AC) (n = 13), and HTLV-1-seronegative individuals (n = 9), with the results analyzed according to the speed of HAM/TSP progression. HAM/TSP patients had elevated fractalkine in the serum but not in the CSF, particularly those with low neuroinflammatory activity (CSF/serum ratio of neopterin <1 and of CXCL10 < 2). HAM/TSP patients with normal CSF levels of neurofilament light chain (NfL) showed elevated ß-NGF in serum, and serum BDNF levels were increased in HTLV-1-infected individuals, particularly in HTLV-1 AC. Both HTLV-1 AC and HAM/TSP patients had lower TGF-ß1 levels in CSF compared to uninfected individuals, and HAM/TSP patients with active CNS inflammation showed higher CSF levels of IL-18, which correlated with markers of inflammation, neuronal death, and blood−brain-barrier permeability. Although none of the factors evaluated were associated with the speed of HAM/TSP progression, reduced TGF-ß1 levels in CSF suggest that suppressive responses to control subclinical and/or active neurodegeneration are impaired, while increased CSF IL-18 indicates the involvement of inflammasome-mediated mechanisms in HAM/TSP development.

Inflammasome activation and assembly in Huntington's disease.

Huntington's disease (HD) is a rare neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Inflammasomes are multiprotein complexes capable of sensing pathogen-associated and damage-associated molecular patterns, triggering innate immune pathways. Activation of inflammasomes results in a pro-inflammatory cascade involving, among other molecules, caspases and interleukins. NLRP3 (nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3) is the most studied inflammasome complex, and its activation results in caspase-1 mediated cleavage of the pro-interleukins IL-1ß and IL-18 into their mature forms, also inducing a gasdermin D mediated form of pro-inflammatory cell death, i.e. pyroptosis. Accumulating evidence has implicated NLRP3 inflammasome complex in neurodegenerative diseases. The evidence in HD is still scant and mostly derived from pre-clinical studies. This review aims to present the available evidence on NLRP3 inflammasome activation in HD and to discuss whether targeting this innate immune system complex might be a promising therapeutic strategy to alleviate its symptoms.

Elevated IL-18 predicts poor prognosis in critically ill COVID-19 patients at a Brazilian hospital in 2020-21.

Background: A dysregulated inflammatory response contributes to decline in patients with COVID-19. This cross-sectional study evaluated biomarkers of unvaccinated patients admitted to the intensive care unit of a hospital in Fortaleza, Brazil. Methods: Twenty cytokines were quantified upon hospital admission; clinical and laboratory data were analyzed, as well as sociodemographic data, to search for an association with clinical outcomes, including fatal (n = 40) or recovered cases (n = 38). Results: Fatal cases exhibited significantly higher levels of IL-18 (p = 0.009); deceased patients were older (p = 0.0001), had a lower number of platelets (p = 0.0063) and higher neutrophil-lymphocyte ratio (p = 0.0230) than those who recovered. Conclusion: These findings indicate that IL-18 is a possible marker to predict poor prognosis in critically ill patients with COVID-19.

Cytotoxic CD4+ T cells driven by T-cell intrinsic IL-18R/MyD88 signaling predominantly infiltrate Trypanosoma cruzi-infected hearts.

Increasing attention has been directed to cytotoxic CD4+ T cells (CD4CTLs) in different pathologies, both in humans and mice. The impact of CD4CTLs in immunity and the mechanisms controlling their generation, however, remain poorly understood. Here, we show that CD4CTLs abundantly differentiate during mouse infection with the intracellular parasite Trypanosoma cruzi. CD4CTLs display parallel kinetics to Th1 cells in the spleen, mediate specific cytotoxicity against cells presenting pathogen-derived antigens and express immunoregulatory and/or exhaustion markers. We demonstrate that CD4CTL absolute numbers and activity are severely reduced in both Myd88-/- and Il18ra-/- mice. Of note, the infection of mixed-bone marrow chimeras revealed that wild-type (WT) but not Myd88-/- cells transcribe the CD4CTL gene signature and that Il18ra-/- and Myd88-/- CD4+ T cells phenocopy each other. Moreover, adoptive transfer of WT CD4+GzB+ T cells to infected Il18ra-/- mice extended their survival. Importantly, cells expressing the CD4CTL phenotype predominate among CD4+ T cells infiltrating the infected mouse cardiac tissue and are increased in the blood of Chagas patients, in which the frequency of CD4CTLs correlates with the severity of cardiomyopathy. Our findings describe CD4CTLs as a major player in immunity to a relevant human pathogen and disclose T-cell intrinsic IL-18R/MyD88 signaling as a key pathway controlling the magnitude of the CD4CTL response.

Increased Serum Levels of Growth-Differentiation Factor 3 (GDF3) and Inflammasome-Related Markers in Pregnant Women during Acute Zika Virus Infection.

The systemic inflammatory response elicited by acute Zika virus (ZIKV) infection during pregnancy plays a key role in the clinical outcomes in mothers and congenitally infected offspring. The present study aimed to evaluate the serum levels of GDF-3 and inflammasome-related markers in pregnant women during acute ZIKV infection. Serum samples from pregnant (n = 18) and non-pregnant (n = 22) women with acute ZIKV infection were assessed for NLRP3, IL-1ß, IL-18, and GDF3 markers through an enzyme-linked immunosorbent assay. ZIKV-negative pregnant (n = 18) and non-pregnant women (n = 15) were used as control groups. All serum markers were highly elevated in the ZIKV-infected groups in comparison with control groups (p < 0.0001). Among the ZIKV-infected groups, the serum markers were significantly augmented in the pregnant women in comparison with non-pregnant women (NLRP3 p < 0.001; IL-1ß, IL-18, and GDF3 p < 0.0001). The IL-18 marker was found at significantly higher levels (p < 0.05) in the third trimester of pregnancy. Bivariate and multivariate analyses showed a strong positive correlation between GDF3 and NLRP3 markers among ZIKV-infected pregnant women (r = 0.91, p < 0.0001). The findings indicated that acute ZIKV infection during pregnancy induces the overexpression of GDF-3 and inflammasome-related markers, which may contribute to congenital disorders and harmful pregnancy outcomes.

The genetics behind inflammasome regulation.

The inflammasome is a cytosolic multiproteic complex that promotes proinflammatory events through the release of the cytokines IL-1ß and IL-18, and in some context by the induction of a lytic cell death called pyroptosis, in response to damage, infections, or changes in the homeostasis. Due to the powerful inflammatory effect, there are several regulatory mechanisms that are essential to modulate or limit the activation of the inflammasome. When these mechanisms fail, the deregulation of the complex leads or contributes to the development of a plethora of diseases characterized by constitutive and/or chronic inflammation, such as autoinflammatory, autoimmune, cardiovascular, neurodegenerative, and metabolic diseases, cancer, or even severe complications of infectious diseases. Either environmental or genetic factors may affect the threshold and/or the level of inflammasome activation, such as hyperglycemia, hyperuricemia, auto-antibodies, unfolded proteins and fibrils, or individual genetic variants in genes coding for inflammasome receptors or effector molecules, and also in regulators. While the genetics of inflammasome itself has been elsewhere characterized and also recently reviewed by our group, less is known about how genetic variants in regulatory molecules could affect inflammatory diseases. Therefore in this work, we selected a group of known or possible regulators of the inflammasome, and through the review of genetic association studies we tried to depict the contribution of these regulators in the development of multifactorial diseases.

The Role of Urinary Biomarkers as Diagnostic and Prognostic Predictors of Acute Kidney Injury Associated With Vancomycin.

Introduction: The incidence of acute kidney injury (AKI) related to vancomycin is variable, and several risk factors related to the treatment and patients may explain the nephrotoxicity. The role of urinary biomarkers in AKI related to vancomycin is unknown. Objective: The aim of this study was to evaluate the role of urinary IL-18, KIM-1, NGAL, TIMP-2, and IGFBP7 as diagnostic and prognostic predictors of AKI related to vancomycin. Methods: A prospective cohort study of patients receiving vancomycin and admitted to wards of a public university hospital from July 2019 to May 2020 was performed. We excluded patients that had AKI before starting vancomycin, hemodynamic instability, inability to collect urine, and chronic kidney disease stage 5. Results: Ninety-four patients were included, and the prevalence of AKI was 24.5%, while the general mortality was 8.7%. AKI occurred 11 ± 2 days after the first vancomycin dose. The most frequent KDIGO stage was 1 (61%). There was no difference between patients who developed and did not develop AKI due to gender, length of hospital stay, dose, and time of vancomycin use. Logistic regression identified age (OR 6.6, CI 1.16-38.22, p = 0.03), plasmatic vancomycin concentrations between 96 and 144 h (OR 1.18, CI 1.04-1.40, p = 0.04), and urinary NGAL levels between 96 and 144 h (OR 1.123, CI 1.096-1.290, p = 0.03) as predictors of AKI. The time of vancomycin use (OR 4.61, CI 1.11-22.02, p = 0.03), higher plasmatic vancomycin concentrations between 192 and 240 h (OR 1.02, CI 0.98-1.06, p = 0.26), and higher cell cycle arrest urinary biomarkers TIMP-2 multiplied by IGFBP-7 between 144 and 192 h (OR 1.33, CI 1.10-1.62, p = 0.02; OR 1.19, CI 1.09-1.39, p = 0.04, respectively) were identified as prognostic factors for non-recovery of kidney function at discharge. Conclusion: AKI related to vancomycin was frequent in patients hospitalized in wards. Age, plasmatic vancomycin concentrations, and NGAL between 96 and 144 h were identified as predictors of AKI related to vancomycin use. Plasmatic vancomycin concentrations and urinary NGAL were predictors of AKI diagnosis within the next 5 days. The urinary biomarkers of cell cycle arrest TIMP-2 and IGFBP-7 and the duration of vancomycin use were associated with non-recovery of kidney function at hospital discharge moment.

The Probiotic Lactobacillus fermentum Biocenol CCM 7514 Moderates Campylobacter jejuni-Induced Body Weight Impairment by Improving Gut Morphometry and Regulating Cecal Cytokine Abundance in Broiler Chickens.

This research was conducted to investigate if the administration of the probiotic Lactobacillus fermentum could influence body weight, intestinal morphometry and the cecal cytokine response in Campylobacter jejuni-infected chickens. Seventy-two 1-day old COBB 500 male chicks were allocated randomly into four experimental groups. (I) Control group (C), in which chicks were left untreated. (II) LB group, treated with L. fermentum. (III) Cj group, infected with C. jejuni and (IV) coexposure group in which both bacteria were administered. Body weight was registered and then all birds were slaughtered; samples from the small intestine and caecum were collected at 4- and 7-days post infection. The experiment lasted eleven days. Villi height and crypt depth ratios of the duodenum, jejunum and ileum were evaluated using appropriate software, while reverse transcription quantitative PCR (RT-qPCR) was utilized for assessing transcript levels of key cecal inflammatory cytokines (IL-1ß, IL-18, IL-17, IL-15, IL13 and IL-4). Campylobacter-infected birds showed lower body weight values than those supplemented with the probiotic; these birds, in turn, proved to be heavier than those reared under control conditions. L. fermentum administration improved morphometrical parameters of the duodenum, jejunum and ileum; in general, villi were larger and crypts deeper than those identified in control conditions. Moreover, the negative effects elicited by C. jejuni were not observed in chickens exposed to the probiotic. Significant differences were also determined with regards to transcript abundance of all evaluated cytokines in the caecum. C. jejuni induced a downregulation of the studied interleukins; however, such a response was heightened by administration of L. fermentum, with an increase rate of transcription that promoted a more effective response to a C. jejuni infection. The effects of experimental treatments proved to vary between sampling points. Conclusively, these results demonstrate that L. fermentum lessens the negative effects elicited by C. jejuni on body weight by alleviating the impact on intestinal morphometry and cecal cytokine response, which ultimately improve chicken growth performance.

A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease.

Background: Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy. Methods: Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR. Results: Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24-0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07-0.97, P = 0.044; and OR = 0.35, 95% CI 0.14-0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class ≥ 2 (OR = 0.21, 95% CI 0.06-0.68, P = 0.009; and OR = 0.48, 95% CI 0.24-0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05-0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23-0.96, P = 0.039), NYHA class ≥ 2 (OR = 0.15, 95% CI 0.06-0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00-0.25, P = 0.001). Digestive involvement was negatively associated with NYHA ≥ 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09-0.47, P < 0.001; and OR = 0.24, 95% CI 0.09-0.62, P = 0.004, respectively). Conclusions: Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.