Association between the major histocompatibility complex (MHC) and the susceptibility/resistance to acquire Chagas' disease has been largely demonstrated. To study the role of candidate genes in this susceptibility/resistance to Chagas, we designed a population-genetic-based case-control approach (chagasic n = 104 and controls n = 60) and tested the presence of genotype and linkage disequilibrium on microsatellite loci establishing specific landmarks for the MHC, interleukin (IL)-2, IL-2Rbeta chain, IL-4, IL-10, and natural resistance-associated mactophage protein 1 (NRAMP1). After demonstrating no genetic stratification among cases and controls (F(st) were not different from 0), we found significant allelic differences among chagasic patients and controls at microsatellite locus D6S291 (MHC) and at the microsatellite pointing out the IL-10. At the MHC, we found significant differences between patients and controls in Hardy-Weinberg equilibrium-expected genotype proportions. Additionally, MHC II-locus-inferred haplotypes in chagasic patients exhibited strong significant departures from the expected proportions predicted by the second Mendelian law. The linkage disequilibrium pattern at MHC involves a region of approximately 10 cM. These results replicate previous analyses and suggest that presence of epistasis between MHC with humoral systems, such as IL-10, could be underlying the susceptibility/resistance to Chagas' disease.
Mannose-binding lectin (MBL) is a lectin complement protein encoded by the MBL2 gene that has an important role in the control of infections caused by intracellular pathogens. However, there is no consensus about the effect of MBL2 polymorphism and MBL levels in leishmaniasis infections. We investigated the implications of MBL2 gene variants as well as MBL serum levels and occurrence of visceral leishmaniosis (VL) caused by Leishmania chagasi. A case-control analytic study was performed on 161 patients with VL and 161 healthy individuals in a northeast region of Brazil. The alleles of exon 1 (MBL2*A, MBL2*B, MBL2*C and MBL2*D) and promoter region (-©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 18 (2): gmr18148 E.L. Silva et al. 2 550L/H,-221Y/X and +4P/Q) were identified by automatic sequencing and the MBL serum levels were determined using an ELISA kit. MBL serum levels were similar in VL patients compared to the healthy controls. Also, allelic, genotype and haplotype frequencies of variants in exon 1 and promoter region did not significantly differ between case and control groups. Overall, our data show that MBL2 polymorphisms within the structural gene as well as the promoter region influence functional MBL serum levels but are not associated with susceptibility to L. chagasi infection in this population. We observed a lack of consensus regarding the association of MBL 2 polymorphisms with leishmaniasis worldwide, indicating that the influence of genetic variations can differ in different populations and with differences in parasite/vector relationship.
Leishmaniasis is a neglected disease that affects millions of people worldwide, and special attention should be given to treatment because the available drugs have limitations, which can lead to low therapeutic adherence and parasitic resistance. This study evaluated the activity of the bioactive naphthoquinones, lapachol and β-lapachone, against Leishmania amazonensis . The cell alterations were evaluated in vitro on promastigote and amastigote forms. The lethal dose (LD 50 ) at 24, 48, and 72 h on the promastigote's forms using lapachol was 75.60, 72.82, and 58.85 μg/mL and for β-lapachone was 0.65, 1.24, and 0.71 μg/mL, respectively. The naphthoquinones significantly inhibited the survival rate of L. amazonensis amastigotes at 83.11, 57.59, and 34.95% for lapachol (82.28, 41.14, and 20.57 µg/mL), and 78.49, 83.25, and 80.22% for β-lapachone (3.26, 1.63, and 0.815 µg/mL). The compounds on the promastigote's forms led to the loss of mitochondrial membrane potential, induced changes in the integrity of the membrane, caused damage to cells suggestive of the apoptotic process, and showed inhibition of tumor necrosis factor (TNF)-α and interleukin (IL)-6 production. The results showed that these naphthoquinones are promising candidates for research on new drugs with anti- Leishmania activity derived from natural products.
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