Genetic polymorphisms associated with the inflammatory response in bacterial meningitis

BACKGROUND Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C > T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G > A, TNF -857C > T, IL-8 -251A > T and BM and investigated gene-gene interactions, including the SNPs that we published previously. METHODS The study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS We did not find significant association between the SNPs TNF -857C > T and IL-8 -251A > T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients. CONCLUSIONS In conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches

Marcadores genéticos associados com a resposta inflamatória na meningite bacteriana

Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorA meningite bacteriana (MB) é uma doença infecto-contagiosa que apresenta altas taxas de mortalidade e morbidade, constituindo-se assim um grave problema de saúde pública. É caracterizada por uma intensa inflamação granulocítica que leva a injúria neuronal e consequentemente surgimento de sequelas neurológicas. A resposta inflamatória determina tanto a susceptibilidade à MB como sua consequência clínica. Essa resposta depende não só do tipo e da intensidade do estímulo, mas também de fatores genéticos do hospedeiro, tais como polimorfismos localizados em regiões codificantes ou regulatórias de genes importantes durante a infecção, dentre os mais frequentes os polimorfismos de um único nucleotídeo (SNPs). O objetivo desse estudo foi investigar a associação entre os polimorfismos em TNF -308G/A, TNF -857C/T, IL-8 -251A/T, AADAT+401C/T, que codificam proteínas importantes durante a resposta inflamatória e APEX1 Asn148Glu, OGG1 Ser326Cys e PARP-1 Val762Ala, que codificam enzimas de reparo de DNA, com a ocorrência da MB. O estudo foi realizado com um grupo de 54 pacientes, admitidos no Hospital Giselda Trigueiro, Natal-RN, Brasil, o qual é referência para doenças infecciosas no estado, e um grupo controle formado por 110 voluntários saudáveis. Todos os indivíduos incluídos no estudo autorizaram o uso do material biológico para a pesquisa através de termo de consentimento. Os genótipos foram investigados por PIRA-PCR ou PCR-RFLP. As frequências alélicas e genotípicas também foram associados com os níveis de cito/quimiocinas, medidas pelo método xMAP, e com os níveis de imunoglobulinas. Não encontramos diferenças significativas na distribuição individual entre pacientes e controles saudáveis das variantes TNF -857C/T e IL8 -251A/T, no entanto, foi observada uma maior frequência do alelo polimórfico TNF-308A (P= 0,0145, OR= 0,34) no grupo controle, sugerindo um possível papel protetor contra a doença. Os portadores do SNP em TNF -308G/A também apresentaram aumento nos níveis de TNF-α (P=0,0515) e IL- 6 (P=0,0135) no grupo MB e para MCP-1 (P=0,0381) e TNF-α (P=0,0547 borderline) no grupo controle. Além disso, a análise de combinação entre os genes estudados mostrou associação significativa para as combinações entre APEX1148Glu/_ com OGG1 326Cys/_ e com PARP-1 762Ala/_ (P= 0,0007, OR=5,35), e IL-8 -251T/ com APEX1148Glu/_ (P= 0,0003, OR= 2,90) que foram mais frequentes em pacientes com MB, os quais afetaram os níveis de cito/quimiocinas e celularidade em amostras de LCR de pacientes com MB. Esse trabalho foi realizado com a contribuição de uma equipe multidisciplinar que envolveu diversos profissionais das ciências biológicas e da saúde, como biólogos, farmacêuticos e médicos. Os nossos dados indicam que a avaliação extensiva da variabilidade genética pode contribuir para uma melhor compreensão da susceptibilidade à MB como também para outras doenças infecciosas que ativam os mesmos mecanismos de resposta imun

Role of Arbovirus Infection in Arthritogenic Pain Manifestation—A Systematic Review

The number of publications on the development of arthritic pain after CHIKV infection is increasing; however, there is still a gap in the pathophysiological mechanisms that explain these outcomes. In this review, we conducted a descriptive analysis of the findings of patients to understand their prognosis and to explore therapeutic options. Here, we searched the Cochrane, BVS, PubMed, and Scielo databases using the keywords “arthritis”, “pain”, “arbovirus”, “disease”, “arthritogenic”, and “arthralgia” during the 2000 to 2022 period. Descriptive analyses were conducted to understand the association between CHIKV infection and arthritogenic pain. The present study shows the persistence of acute phase signals for months, making the chronic phase still marked by the presence of arthralgia, often disabling under stimuli, such as temperature variation. CHIKV infection appears to be remarkably similar to rheumatoid arthritis, since both diseases share common symptoms. Once diagnosed, patients are mostly treated with analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease modifying anti-rheumatic drugs (DMARD). As there are no prophylactic measures or specific treatments for arboviruses, this study gathered information on the development and manifestations of arthritogenic pain

Endocannabinoid System: Chemical Characteristics and Biological Activity

The endocannabinoid system (eCB) has been studied to identify the molecular structures present in Cannabis sativa. eCB consists of cannabinoid receptors, endogenous ligands, and the associated enzymatic apparatus responsible for maintaining energy homeostasis and cognitive processes. Several physiological effects of cannabinoids are exerted through interactions with various receptors, such as CB1 and CB2 receptors, vanilloid receptors, and the recently discovered G-protein-coupled receptors (GPR55, GPR3, GPR6, GPR12, and GPR19). Anandamide (AEA) and 2-arachidoylglycerol (2-AG), two small lipids derived from arachidonic acid, showed high-affinity binding to both CB1 and CB2 receptors. eCB plays a critical role in chronic pain and mood disorders and has been extensively studied because of its wide therapeutic potential and because it is a promising target for the development of new drugs. Phytocannabinoids and synthetic cannabinoids have shown varied affinities for eCB and are relevant to the treatment of several neurological diseases. This review provides a description of eCB components and discusses how phytocannabinoids and other exogenous compounds may regulate the eCB balance. Furthermore, we show the hypo- or hyperfunctionality of eCB in the body and how eCB is related to chronic pain and mood disorders, even with integrative and complementary health practices (ICHP) harmonizing the eCB

Additional file 1: Table S1. of Genetic polymorphisms associated with the inflammatory response in bacterial meningitis

Allelic and genotypic frequencies of the SNPs in the studied population. Figure S1. Haplotype map showing the two TNF analyzed polymorphism and a D’ value of 0.11, suggesting that the TNF polymorphisms segregate independently (linkage equilibrium). Figure S2. Cytokine and chemokine concentration in relation to the genotype for SNP TNF -308G>A. (A): CSF samples of BM patients. (B): Plasma samples of controls. Figure S3. Cyto/chemokine concentration in CSF samples in relation to the combination of genotypes in BM patients. (A): APEX1 148Glu/_ plusIL8 -251 T/_ combination. (B): APEX1 148Glu/_ plus OGG1 326Cys/_ and PARP1 l762Ala/_ combination. (C): IL8 T/_ plus APEX1Glu/_ and AADATT/_combination. (D): APEX1 148 Glu/_ plus AADAT +401 T/_ combination. (E): APEX1 148Glu/_ and OGG1 326Cys/_ combination. (F): TNF −308 GG plusIL8 T/_ plus APEX1Glu/_ and AADATT/_ combination. Figure S4. Cyto/chemokine concentration in Plasma samples in relation to the combination of genotypes in controls. (A): APEX1 148Glu/_ plusIL8 -251 T/_ combination. (B): APEX1 148 Glu/_ plus AADAT +401 T/_ combination. (C): IL8 T/_ plus APEX1Glu/_ and AADATT/_ combination. It was not possible to compare all combinations in this biological sample due to the small amount of material. Figure S5. Cell count in CSF samples in relation to the combination of genotypes in BM patients: (A): APEX1 148Glu/_ plus OGG1 326Cys/_ and PARP1 l762Ala/_ combination. (B): IL8 T/_ plus APEX1 Glu/_ and AADATT/_ combination. (C): APEX1 148Glu/_ andOGG1 326Cys/_ combination. (D): TNF −308 GG plusIL8 T/_ plus APEX1Glu/_ and AADATT/_ combination. (DOCX 773 kb

The kynurenine pathway is involved in bacterial meningitis.

BackgroundBacterial meningitis (BM) is characterized by an intense host inflammatory reaction, which contributes to the development of brain damage and neuronal sequelae. Activation of the kynurenine (KYN) pathway (KP) has been reported in various neurological diseases as a consequence of inflammation. Previously, the KP was shown to be activated in animal models of BM, and the association of the SNP AADAT¿+¿401C/T (kynurenine aminotransferase II - KAT II) with the host immune response to BM has been described. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups.MethodsThe concentrations of tryptophan (TRP), KYN, kynurenic acid (KYNA) and anthranilic acid (AA) were assessed by HPLC from CSF samples of patients hospitalized in the Giselda Trigueiro Hospital in Natal (Rio Grande do Norte, Brazil). The KYN/TRP ratio was used as an index of indoleamine 2,3-dioxygenase (IDO) activity, and cytokines were measured using a multiplex cytokine assay. The KYNA level was also analyzed in relation to AADAT¿+¿401C/T genotypes.ResultsIn CSF from patients with BM, elevated levels of KYN, KYNA, AA, IDO activity and cytokines were observed. The cytokines INF-¿ and IL-1Ra showed a positive correlation with IDO activity, and TNF-¿ and IL-10 were positively correlated with KYN and KYNA, respectively. Furthermore, the highest levels of KYNA were associated with the AADAT¿+¿401 C/T variant allele.ConclusionThis study suggests a downward modulatory effect of the KP on CSF inflammation during BM

SNPs in DNA repair genes associated to meningitis and host immune response

In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis

Polymorphisms in the CIITA −168A/G (rs3087456) and CIITA +1614G/C (rs4774) may influence severity in multiple sclerosis patients

ABSTRACT It is currently unknown how genetic factors may influence the clinical course of multiple sclerosis (MS). Objective: We examined the impact of CIITA polymorphisms −168A/G (rs3087456) and +1614G/C (rs4774) on the risk of disability progression, severity and on responses to first-line immunomodulator treatments. Methods: Genomic DNA was extracted from blood samples. We used ABI3730xl and GeneMapper v.4.0 software to identify genotype variations. All patients were followed up and clinically reassessed at three-month intervals. Disability progression was measured by the Expanded Disability Status Scale and disease severity by the Multiple Sclerosis Spasticity Scale (MSSS). Results: We included 37 men and 80 women. We found no evidence regarding the influence of the single nucleotide polymorphisms studied in the Expanded Disability Status Scale or therapeutic response of the evaluated drugs. We performed a logistic regression analysis with the MSSS and found that a less severe MS course was associated with wild type CIITA −168AA and CIITA +1614GG, as the chance of the patient progressing to MSSS2 and MSSS3 decreased in 61% and 75% with CIITA −168AA and 66% and 75% with CIITA +1614GG, respectively (p < 0.0001). Although less significant, the CIITA +1614 GC also pointed to a less severe MS course and the chance of the patient progressing to MSSS3 decreased 79% (p = 0.015). We also observed that the CIITA −168GG genotype was more frequent in MSSS2 and MSSS3 and had 40% lower odds ratio to becoming more severe MS. Conclusion: These data suggest that CIITA −168AA, CIITA +1614GG and CIITA +1614 GC polymorphisms may be associated with a better MS clinical course. This knowledge may be useful for a better understanding of MS and its therapeutic management