Enhanced IL-6 and IL-12B Gene Expression After SARS-CoV-2 Infection in Leprosy Patients May Increase the Risk of Neural Damage.

Experts have called attention to the possible negative impact of the coronavirus disease 2019 (COVID-19)-related cytokine storm syndrome on the progression of leprosy-related disabilities. We assessed the frequency of reactional states in patients co-infected with Mycobacterium leprae and severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS-CoV-2). We consecutively included patients during the first peak of the COVID-19 epidemic in Brazil and analyzed the expressions of genes encoding interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12A, IL-12B, and tumor necrosis factor-α in peripheral blood mononuclear cells. We included 64 leprosy patients and 50 controls. Twelve of the leprosy patients and 14 of the controls had been diagnosed with COVID-19. Co-infection was associated with increased IL-6 (P = 0.043) and IL-12B (P = 0.017) expression. The median disability grades were higher for leprosy/COVID-19 patients; however, the difference was not significant (P = 0.194). Patients co-infected with M. leprae and SARS-CoV-2 may experience a higher-grade proinflammatory state.

Study of TNF-α, IFN-γ, TGF-ß, IL-6, and IL-10 Gene Polymorphism in Individuals from the Leprosy-Endemic Area in the Brazilian Amazon.

This study aimed at verifying the relationship between the polymorphisms of the cytokines tumor necrosis factor-alpha (TNF-α) -308 G → A (rs1800629); interferon gamma (IFN-γ) +874 T → A (rs2430561); transforming growth factor-beta (TGF-ß) códon 10 (rs1982073) and códon 25 (rs1800471); interleukin (IL)-6 - 174 G → C (rs180079) and IL-10 - 1082 A→T (rs1800896); -819 C → T (rs1800871); -592 A→C (rs1800872); and leprosy. Blood samples were analyzed from 106 individuals, of whom 24 were paucibacillary (PB), 28 were multibacillary (MB), and 54 were patient contacts. Analysis of cytokine polymorphisms was typified by the polymerase chain reaction technique. For TGF-ß +869 T → C and +915 G→C, a tendency to associate the presence of the C allele at codon 10 with leprosy was demonstrated, with the T allele being most frequently found in the CCOSI (P = 0.056). For the polymorphisms IL-10 - 1082 A→T, -819 C→T, and -592 A→C, we found an association of the GCC/GCC genotype with the susceptibility to the disease and the A allele at position 1082 with the leprosy protection. Greater predominance was found of ACC/ATA (31.3%) and GCC/ATA (37.5%) (P = 0.03) and the A allele at position -1082 (76.85%) (P = 0.043) in the CCOSI groups, whereas the GCC/GCC was found in the MB group (22.2%) (P = 0.05). For the other cytokines's single-nucleotide polymorphisms, there were no associations with susceptibility to leprosy. These results are limited by sample size, may not be conclusive, and will need further confirmation in a larger cohort.

Photoperiod Affects Leptin Action on the Choroid Plexus in Ewes Challenged with Lipopolysaccharide-Study on the mRNA Level.

The ovine choroid plexus (ChP) expresses the long isoform of the leptin receptor, which makes this structure a potential target for leptin action. In sheep, leptin concentration in plasma is higher during long days (LD) than short days (SD). This study evaluates the influence a of photoperiod on leptin impact on the gene expression of Toll-like receptor 4 (TLR4), proinflammatory cytokines (IL1B, IL6), their receptors (IL1R1, IL1R2, ILRN, IL6R, IL6ST) and inflammasome components necessary for pro-IL-1ß activation (NLRP3, PYCARD, CASP1), chemokine (CCL2), leptin receptor isoforms (LEPRa, LEPRb) and a suppressor of cytokine signalling (SOCS3) in the ChP of ewes treated or not with lipopolysaccharide (LPS). Studies were conducted on adult female sheep divided into four groups (n = 6 in each): control, leptin (20 µg/kg), LPS (400 ng/kg), and LPS and leptin injected under SD and LD photoperiods. The leptin alone did not affect the gene expression but in co-treatment with LPS increased (p < 0.05) IL1B but only during SD, and SOCS3, IL1R2, IL1RN, IL6ST and CCL2 only during LD, and decreased (p < 0.05) the IL1R1 expression only during SD photoperiod. This indicates that the immunomodulatory action of leptin on the ChP is manifested only under the LPS challenge and is photoperiodically dependent.

Genetic polymorphisms of the IL6 and NOD2 genes are risk factors for inflammatory reactions in leprosy.

The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan-Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-γ levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.

Expression of interleukin-1ß and interleukin-6 in leprosy reactions in patients with human immunodeficiency virus coinfection.

Previous studies suggest that coinfection of leprosy and human immunodeficiency virus (HIV) does not decrease the frequency and intensity of leprosy reactions. However, the immunological aspects of leprosy reactions in coinfected patients remain obscure, with a limited number of studies showing contradictory results. Observational study using tissue samples collected during leprosy reactions from 15 patients coinfected with leprosy and HIV and from 15 patients with leprosy alone. Patients were part of a prior larger cohort study of leprosy patients with and without HIV coinfection. Specific antibodies were used to detect IL-1ß and IL-6 expression in skin biopsy tissue cells. IL-1ß and IL-6 expression was similar between leprosy patients with and without HIV coinfection (p>0.05). Coinfected and non-coinfected tissues showed similar levels of IL-1ß and IL-6 expression for type 1 reactions. A trend towards increased levels of IL-1ß and IL-6 expression was observed in tissue from coinfected patients (p=0.0024). The expression of IL-1ß and IL-6 during leprosy reactions did not differ significantly between tissues obtained from leprosy patients with and without HIV coinfection. Therefore, we conclude that HIV coinfection does not affect the immunological pattern of leprosy reactions.

Early secreted antigen ESAT-6 of Mycobacterium Tuberculosis promotes apoptosis of macrophages via targeting the microRNA155-SOCS1 interaction.

BACKGROUND: The early secreted antigenic target 6-kDa protein (ESAT-6) of Mycobacterium tuberculosis (Mtb) not only acts as a key player for virulence but also exhibits a strong immunotherapeutic potential against Mtb. However, little is known about the molecular basis for its potential in immunotherapy. The present study was designed to unravel the role of miRNA-155 in ESAT-6-mediated enhancement of host immunity and apoptosis in macrophages. METHODS: Lentivirus-mediated miR-155 sponge and miR-155 and SOCS1 overexpression vectors were developed in macrophages. TLR2- or p65-specific siRNA knockdown was employed to silence TLR2 or p65. Quantitative polymerase chain reaction and western blotting analyses were performed to determine mRNA and protein expression levels, respectively. Macrophage apoptosis was analyzed by flow cytometry. RESULTS: ESAT-6 significantly increased miR-155 expression, which was dependent on TLR2/NF-κB activation in macrophages. Induced expression of miRNA-155 was required for the ESAT-6-mediated protective immune response and macrophage apoptosis. ESAT-6 promoted macrophage apoptosis by targeting the miR-155-SOCS1 pathway. The differential expression levels of TLR2, BIC, and SOCS1 were involved in regulating the immune response in human peripheral blood mononuclear cells of patients with active tuberculosis (TB) and latent TB (LTB). CONCLUSION: ESAT-6 promotes apoptosis of macrophages via targeting the miRNA155-SOCS1 interaction.

Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction.

In leprosy, type 1 reaction (T1R) and type 2 reaction (T2R) are major causes of nerve injury and permanent disabilities. A previous study on plasma levels of 27 cytokines in patients with T1R or T2R and controls with nonreactional leprosy identified the gene for interleukin 6 (IL-6) as a candidate for genetic analysis. Two nested case-control studies were built from a cohort of 409 patients with leprosy from central Brazil, monitored for T1R and T2R. There was evidence for association between T2R and IL-6 tag single-nucleotide polymorphisms rs2069832 (P = .002), rs2069840 (P = .03), and rs2069845 (P = .04), with information on the entire IL-6 locus, as well as functional IL-6 variant rs1800795 (P = .005). Moreover, IL-6 plasma levels in patients with T2R correlated with IL-6 genotypes (P = .04). No association was found between IL-6 variants and T1R. Identifying genetic predictive factors for leprosy reactions may have a major impact on preventive strategies.