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1.
Int J Mol Sci ; 25(18)2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39337535

ABSTRACT

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1-/- knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.


Subject(s)
Kidney Tubules, Collecting , Receptors, Cell Surface , Sodium , Up-Regulation , Animals , Mice , Kidney Tubules, Collecting/metabolism , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Male , Sodium/metabolism , Hypertension, Renovascular/metabolism , Hypertension, Renovascular/genetics , Blood Pressure , Mice, Knockout , Prorenin Receptor , Kidney/metabolism , Disease Models, Animal , Renin-Angiotensin System , Mice, Inbred C57BL , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, Purinergic P2
2.
Front Immunol ; 15: 1462853, 2024.
Article in English | MEDLINE | ID: mdl-39346907

ABSTRACT

Macrophages play a pivotal role in tissue homeostasis, pathogen defense, and inflammation resolution. M1 and M2 macrophage phenotypes represent two faces in a spectrum of responses to microenvironmental changes, crucial in both physiological and pathological conditions. Neuraminidase 1 (Neu1), a lysosomal and cell surface sialidase responsible for removing terminal sialic acid residues from glycoconjugates, modulates several macrophage functions, including phagocytosis and Toll-like receptor (TLR) signaling. Current evidence suggests that Neu1 expression influences M1/M2 macrophage phenotype alterations in the context of cardiovascular diseases, indicating a potential role for Neu1 in macrophage polarization. For this reason, we investigated the impact of Neu1 deficiency on macrophage polarization in vitro and in vivo. Using bone marrow-derived macrophages (BMDMs) and peritoneal macrophages from Neu1 knockout (Neu1-/- ) mice and wild-type (WT) littermate controls, we demonstrated that Neu1-deficient macrophages exhibit an aberrant M2-like phenotype, characterized by elevated macrophage mannose receptor 1 (MMR/CD206) expression and reduced responsiveness to M1 stimuli. This M2-like phenotype was also observed in vivo in peritoneal and splenic macrophages. However, lymph node (LN) macrophages from Neu1-/- mice exhibited phenotypic alterations with reduced CD206 expression. Further analysis revealed that peripheral LNs from Neu1-/- mice were highly fibrotic, with overexpression of transforming growth factor-beta 1 (TGF-ß1) and hyperactivated TGF-ß signaling in LN macrophages. Consistently, TGF-ß1 was found to alter M1/M2 macrophage polarization in vitro. Our findings showed that Neu1 deficiency prompts macrophages towards an M2 phenotype and that microenvironmental changes, particularly increased TGF-ß1 in fibrotic tissues such as peripheral LNs in Neu1-/- mice, further influence M1/M2 macrophage polarization, highlighting its sensitivity to the local microenvironment. Therapeutic interventions targeting Neu1 or TGF-ß signaling pathways may offer the potential to regulate macrophage behavior across different diseases.


Subject(s)
Cellular Microenvironment , Fibrosis , Lymph Nodes , Macrophages , Mice, Knockout , Neuraminidase , Animals , Mice , Macrophages/immunology , Macrophages/metabolism , Lymph Nodes/immunology , Lymph Nodes/metabolism , Lymph Nodes/pathology , Neuraminidase/deficiency , Neuraminidase/genetics , Neuraminidase/metabolism , Mice, Inbred C57BL , Macrophage Activation , Lectins, C-Type/metabolism , Lectins, C-Type/genetics , Lectins, C-Type/deficiency , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Cells, Cultured , Signal Transduction , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/deficiency , Mannose Receptor , Phenotype , Transforming Growth Factor beta1/metabolism
3.
Arch Insect Biochem Physiol ; 116(3): e22125, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38973236

ABSTRACT

Insect pest control can be achieved by the application of RNA interference (RNAi), a key molecular tool in functional genomics. Whereas most RNAi research has focused on insect pests, few studies have been performed on natural enemies. Validating the efficacy of RNAi in natural enemies is crucial for assessing its safety and enabling molecular research on these organisms. Here, we assessed the efficacy of RNAi in the ladybird beetle Eriopis connexa Germar (Coleoptera: Coccinellidae), focusing on genes related to reproduction, such as vitellogenin (Vg) and its receptor (VgR). In the transcriptome of E. connexa, we found one VgR (EcVgR) and two Vg genes (EcVg1 and EcVg2). These genes have been validated by in silico analyses of functional domains and evolutionary relationships. Five-day-old females were injected with 500 ng/µL of a specific double-stranded RNA (dsRNA) (dsEcVg1, dsEcVg2, or dsEcVgR) for RNAi tests, while nonspecific dsRNA (dsGFP or dsAgCE8.1) was used as a control. Interestingly, dsEcVg2 was able to knockdown both Vg genes, while dsEcVg1 could silence only EcVg1. Additionally, the viability of the eggs was significantly reduced when both Vg genes were knocked down at the same time (after treatment with dsEcVg2 or "dsEcVg1+dsEcVg2"). Ultimately, malformed, nonviable eggs were produced when EcVgR was silenced. Interestingly, no dsRNA treatment had an impact on the quantity of eggs laid. Therefore, the feasibility of RNAi in E. connexa has been confirmed, suggesting that this coccinellid is an excellent Neotropical model for molecular research on natural enemies and for studying RNAi nontarget effects.


Subject(s)
Coleoptera , Gene Knockdown Techniques , RNA Interference , Animals , Coleoptera/genetics , Female , Vitellogenins/genetics , Vitellogenins/metabolism , Insect Proteins/genetics , Insect Proteins/metabolism , Reproduction/genetics , RNA, Double-Stranded/genetics , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Egg Proteins/genetics , Egg Proteins/metabolism , Pest Control, Biological
4.
Arch Insect Biochem Physiol ; 116(1): e22120, 2024 May.
Article in English | MEDLINE | ID: mdl-38739744

ABSTRACT

The vitellogenin receptor (VgR) is essential for the uptake and transport of the yolk precursor, vitellogenin (Vg). Vg is synthesized in the fat body, released in the hemolymph, and absorbed in the ovaries, via receptor-mediated endocytosis. Besides its important role in the reproductive pathway, Vg occurs in nonreproductive worker honey bee, suggesting its participation in other pathways. The objective was to verify if the VgR occurs in the hypopharyngeal glands of Apis mellifera workers and how Vg is internalized by these cells. VgR occurrence in the hypopharyngeal glands was evaluated by qPCR analyses of VgR and immunohistochemistry in workers with different tasks. The VgR gene is expressed in the hypopharyngeal glands of workers with higher transcript levels in nurse honey bees. VgR is more expressed in 11-day-old workers from queenright colonies, compared to orphan ones. Nurse workers with developed hypopharyngeal glands present higher VgR transcripts than those with poorly developed glands. The immunohistochemistry results showed the co-localization of Vg, VgR and clathrin (protein that plays a major role in the formation of coated vesicles in endocytosis) in the hypopharyngeal glands, suggesting receptor-mediated endocytosis. The results demonstrate that VgR performs the transport of Vg to the hypopharyngeal glands, supporting the Ovary Ground Plan Hypothesis and contributing to the understanding of the role of this gland in the social context of honey bees.


Subject(s)
Egg Proteins , Hypopharynx , Insect Proteins , Receptors, Cell Surface , Animals , Bees/metabolism , Bees/genetics , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Insect Proteins/metabolism , Insect Proteins/genetics , Egg Proteins/metabolism , Egg Proteins/genetics , Hypopharynx/metabolism , Female , Vitellogenins/metabolism , Vitellogenins/genetics , Clathrin/metabolism
5.
Front Immunol ; 15: 1366125, 2024.
Article in English | MEDLINE | ID: mdl-38715615

ABSTRACT

Introduction: Patients with the multibacillary form of leprosy can develop reactional episodes of acute inflammation, known as erythema nodosum leprosum (ENL), which are characterized by the appearance of painful cutaneous nodules and systemic symptoms. Neutrophils have been recognized to play a role in the pathogenesis of ENL, and recent global transcriptomic analysis revealed neutrophil-related processes as a signature of ENL skin lesions. Methods: In this study, we expanded this analysis to the blood compartment, comparing whole blood transcriptomics of patients with non-reactional lepromatous leprosy at diagnosis (LL, n=7) and patients with ENL before administration of anti-reactional treatment (ENL, n=15). Furthermore, a follow-up study was performed with patients experiencing an ENL episode at the time of diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Validation in an independent cohort (ENL=8; LL=7) was performed by RT-qPCR. Results: An enrichment of neutrophil activation and degranulation-related genes was observed in the ENL group, with the gene for the neutrophil activation marker CD177 being the most enriched gene of ENL episode when compared to its expression in the LL group. A more pro-inflammatory transcriptome was also observed, with increased expression of genes related to innate immunity. Validation in an independent cohort indicated that S100A8 expression could discriminate ENL from LL. Supernatants of blood cells stimulated in vitro with Mycobacterium leprae sonicate showed higher levels of CD177 compared to the level of untreated cells, indicating that the leprosy bacillus can activate neutrophils expressing CD177. Of note, suggestive higher CD177 protein levels were found in the sera of patients with severe/moderate ENL episodes when compared with patients with mild episodes and LL patients, highlighting CD177 as a potential systemic marker of ENL severity that deserves future confirmation. Furthermore, a follow-up study was performed with patients at the time of ENL diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Enrichment of neutrophil pathways was sustained in the transcriptomic profile of patients undergoing treatment; however, important immune targets that might be relevant to the effect of thalidomide at a systemic level, particularly NLRP6 and IL5RA, were revealed. Discussion: In conclusion, our study reinforces the key role played by neutrophils in ENL pathogenesis and shed lights on potential diagnostic candidates and novel therapeutic targets that could benefit patients with leprosy.


Subject(s)
Erythema Nodosum , Gene Expression Profiling , Leprosy, Lepromatous , Neutrophil Activation , Neutrophils , Transcriptome , Humans , Erythema Nodosum/immunology , Erythema Nodosum/blood , Leprosy, Lepromatous/immunology , Leprosy, Lepromatous/diagnosis , Leprosy, Lepromatous/blood , Adult , Male , Neutrophils/immunology , Neutrophils/metabolism , Female , Middle Aged , GPI-Linked Proteins/genetics , Thalidomide , Receptors, Cell Surface/genetics , Leprostatic Agents/therapeutic use , Leprostatic Agents/pharmacology , Young Adult , Biomarkers , Isoantigens
6.
J Mol Biol ; 436(11): 168577, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38642883

ABSTRACT

The Red Queen Hypothesis (RQH), derived from Lewis Carroll's "Through the Looking-Glass", postulates that organisms must continually adapt in response to each other to maintain relative fitness. Within the context of host-pathogen interactions, the RQH implies an evolutionary arms race, wherein viruses evolve to exploit hosts and hosts evolve to resist viral invasion. This study delves into the dynamics of the RQH in the context of virus-cell interactions, specifically focusing on virus receptors and cell receptors. We observed multiple virus-host systems and noted patterns of co-evolution. As viruses evolved receptor-binding proteins to effectively engage with cell receptors, cells countered by altering their receptor genes. This ongoing mutual adaptation cycle has influenced the molecular intricacies of receptor-ligand interactions. Our data supports the RQH as a driving force behind the diversification and specialization of both viral and host cell receptors. Understanding this co-evolutionary dance offers insights into the unpredictability of emerging viral diseases and potential therapeutic interventions. Future research is crucial to dissect the nuanced molecular changes and the broader ecological consequences of this ever-evolving battle. Here, we combine phylogenetic inferences, structural modeling, and molecular dynamics analyses to describe the epidemiological characteristics of major Brazilian DENV strains that circulated from 1990 to 2022 from a combined perspective, thus providing us with a more detailed picture on the dynamics of such interactions over time.


Subject(s)
Cell Adhesion Molecules , Dengue Virus , Evolution, Molecular , Host-Pathogen Interactions , Receptors, Cell Surface , Viral Envelope Proteins , Viral Envelope , Humans , Brazil , Cell Adhesion Molecules/metabolism , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/chemistry , Dengue/virology , Dengue Virus/genetics , Dengue Virus/metabolism , Host-Pathogen Interactions/genetics , Lectins, C-Type/metabolism , Lectins, C-Type/genetics , Lectins, C-Type/chemistry , Molecular Dynamics Simulation , Phylogeny , Protein Binding , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/chemistry , Receptors, Virus/metabolism , Receptors, Virus/chemistry , Receptors, Virus/genetics , Viral Envelope/metabolism , Viral Envelope Proteins/genetics , Viral Envelope Proteins/metabolism , Viral Envelope Proteins/chemistry
7.
Pediatr Nephrol ; 39(9): 2633-2636, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38502226

ABSTRACT

BACKGROUND: Nephrocalcinosis (NC) is characterized by an excessive accumulation of calcium deposits in the kidneys. In children, it is often incidentally discovered with an uncertain prognosis. CASE-DIAGNOSIS/TREATMENT: A 3-month-old girl suspected to have a milk protein allergy underwent an ultrasound that revealed increased echogenicity in the kidney pyramids suggestive of medullary NC. At the age of 18 months, imaging findings revealed not only hyperechogenicity in the medulla but also in the cortex. Over the course of a long follow-up, her kidneys maintained size within the upper limits but showed an increase by age 7. Genetic analysis identified PKHD1 variants, which required structural predictive tools to guide clinical diagnosis. Until the age of 7, her kidney function has remained intact; however, her prognosis is uncertain. CONCLUSIONS: NC in newborns is a rare condition, but its incidence is rising. Recurrent urinary infections or kidney stones may lead to kidney failure. A proactive approach in sporadic NC enables an early diagnosis to orientate clinical supervision and facilitates counseling to support family planning decisions.


Subject(s)
Nephrocalcinosis , Humans , Female , Nephrocalcinosis/genetics , Nephrocalcinosis/diagnostic imaging , Nephrocalcinosis/diagnosis , Infant , Receptors, Cell Surface/genetics , Ultrasonography/methods , Kidney/diagnostic imaging , Kidney/abnormalities , Kidney/pathology , Mutation
8.
Mol Ecol ; 33(5): e17263, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38318732

ABSTRACT

The absence of robust interspecific isolation barriers among pantherines, including the iconic South American jaguar (Panthera onca), led us to study molecular evolution of typically rapidly evolving reproductive proteins within this subfamily and related groups. In this study, we delved into the evolutionary forces acting on the zona pellucida (ZP) gamete interaction protein family and the sperm-oocyte fusion protein pair IZUMO1-JUNO across the Carnivora order, distinguishing between Caniformia and Feliformia suborders and anticipating few significant diversifying changes in the Pantherinae subfamily. A chromosome-resolved jaguar genome assembly facilitated coding sequences, enabling the reconstruction of protein evolutionary histories. Examining sequence variability across more than 30 Carnivora species revealed that Feliformia exhibited significantly lower diversity compared to its sister taxa, Caniformia. Molecular evolution analyses of ZP2 and ZP3, subunits directly involved in sperm-recognition, unveiled diversifying positive selection in Feliformia, Caniformia and Pantherinae, although no significant changes were linked to sperm binding. Structural cross-linking ZP subunits, ZP4 and ZP1 exhibited lower levels or complete absence of positive selection. Notably, the fusion protein IZUMO1 displayed prominent positive selection signatures and sites in basal lineages of both Caniformia and Feliformia, extending along the Caniformia subtree but absent in Pantherinae. Conversely, JUNO did not exhibit any positive selection signatures across tested lineages and clades. Eight Caniformia-specific positive selected sites in IZUMO1 were detected within two JUNO-interaction clusters. Our findings provide for the first time insights into the evolutionary trajectories of ZP proteins and the IZUMO1-JUNO gamete interaction pair within the Carnivora order.


Subject(s)
Caniformia , Carnivora , Panthera , Animals , Male , Receptors, Cell Surface/genetics , Egg Proteins/genetics , Egg Proteins/chemistry , Egg Proteins/metabolism , Semen/metabolism , Sperm-Ovum Interactions/genetics , Carnivora/genetics , Caniformia/metabolism , Feliformia/metabolism , Panthera/metabolism , Zona Pellucida/metabolism
9.
Rev Assoc Med Bras (1992) ; 69(11): e20230334, 2023.
Article in English | MEDLINE | ID: mdl-37909612

ABSTRACT

OBJECTIVE: Autosomal dominant polycystic kidney disease is an inherited kidney disorder with mutations in polycystin-1 or polycystin-2. Autosomal recessive polycystic kidney disease is a severe form of polycystic kidney disease that is characterized by enlarged kidneys and congenital hepatic fibrosis. Mutations at PKHD1 are responsible for all typical forms of autosomal recessive polycystic kidney disease. METHODS: We evaluated the children diagnosed with polycystic kidney disease between October 2020 and May 2022. The diagnosis was established by family history, ultrasound findings, and/or genetic analysis. The demographic, clinical, and laboratory findings were evaluated retrospectively. RESULTS: There were 28 children (male/female: 11:17) evaluated in this study. Genetic analysis was performed in all patients (polycystin-1 variants in 13, polycystin-2 variants in 7, and no variants in 8 patients). A total of 18 variants in polycystin-1 and polycystin-2 were identified and 9 (50%) of them were not reported before. A total of eight novel variants were identified as definite pathogenic or likely pathogenic mutations. There was no variant detected in the PKDH1 gene. CONCLUSION: Our results highlighted molecular features of Turkish children with polycystic kidney disease and demonstrated novel variations that can be utilized in clinical diagnosis and prognosis.


Subject(s)
Polycystic Kidney, Autosomal Recessive , Humans , Male , Child , Female , Polycystic Kidney, Autosomal Recessive/genetics , Polycystic Kidney, Autosomal Recessive/diagnosis , Polycystic Kidney, Autosomal Recessive/pathology , TRPP Cation Channels/genetics , Retrospective Studies , Receptors, Cell Surface/genetics , Kidney/pathology , Mutation
10.
J Genet ; 1022023.
Article in English | MEDLINE | ID: mdl-36814109

ABSTRACT

The single-nucleotide polymorphisms (SNP) ILDR1 rs2332035 has shown a high statistical association with presbycusis (hearing loss with age or age-related hearing impairment (ARHI)), according to genetic association studies in European populations. However, linked markers have not been surveyed. Here linkage disequilibrium (LD) of markers in ILDR1, in relation to rs2332035, is explored in the 2504 individuals from the 1000Genomes database. Of the 920 SNPs retrieved, 10 showed strong LD (r2= 0.8) in Europeans and Latin Americans, which are proposed here as candidate markers for both control-case association and cause-effect studies in both populations.


Subject(s)
Polymorphism, Single Nucleotide , Presbycusis , Receptors, Cell Surface , Humans , Genetic Association Studies , Genotype , Linkage Disequilibrium , Presbycusis/genetics , Receptors, Cell Surface/genetics
11.
J Med Virol ; 95(1): e28427, 2023 01.
Article in English | MEDLINE | ID: mdl-36571274

ABSTRACT

The immune response is crucial for coronavirus disease 19 (COVID-19) progression, with the participation of proinflammatory cells and cytokines, inducing lung injury and loss of respiratory function. CLEC5A expression on monocytes can be triggered by viral and bacterial infections, leading to poor outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to induce neutrophil activation by CLEC5A and Toll-like receptor 2, leading to an aggressive inflammatory cascade, but little is known about the molecular interactions between CLEC5A and SARS-CoV-2 proteins. Here, we aimed to explore how CLEC5A expression could be affected by SARS-CoV-2 infection using immunological tools with in vitro, in vivo, and in silico assays. The findings revealed that high levels of CLEC5A expression were found in monocytes from severe COVID-19 patients in comparison with mild COVID-19 and unexposed subjects, but not in vaccinated subjects who developed mild COVID-19. In hamsters, we detected CLEC5A gene expression during 3-15 days of Omicron strain viral challenge. Our results also showed that CLEC5A can interact with SARS-CoV-2, promoting inflammatory cytokine production, probably through an interaction with the receptor-binding domain in the N-acetylglucosamine binding site (NAG-601). The high expression of CLEC5A and high levels of proinflammatory cytokine production were reduced in vitro by a human CLEC5A monoclonal antibody. Finally, CLEC5A was triggered by spike glycoprotein, suggesting its involvement in COVID-19 progression; therapy with a monoclonal antibody could be a good strategy for COVID-19 treatment, but vaccines are still the best option to avoid hospitalization/deaths.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , COVID-19 Drug Treatment , Spike Glycoprotein, Coronavirus , Cytokines , Antibodies, Monoclonal , Glycoproteins , Receptors, Cell Surface/genetics , Lectins, C-Type/genetics
12.
PLoS Negl Trop Dis ; 16(6): e0010493, 2022 06.
Article in English | MEDLINE | ID: mdl-35714097

ABSTRACT

Plasmodium vivax blood-stage invasion into reticulocyte is critical for parasite development. Thus, validation of novel parasite invasion ligands is essential for malaria vaccine development. Recently, we demonstrated that EBP2, a Duffy binding protein (DBP) paralog, is antigenically distinct from DBP and could not be functionally inhibited by anti-DBP antibodies. Here, we took advantage of a small outbreak of P.vivax malaria, located in a non-malarious area of Brazil, to investigate for the first time IgM/IgG antibodies against EBP2 and DEKnull-2 (an engineering DBPII vaccine) among individuals who had their first and brief exposure to P.vivax (16 cases and 22 non-cases). Our experimental approach included 4 cross sectional surveys at 3-month interval (12-month follow-up). The results demonstrated that while a brief initial P.vivax infection was not efficient to induce IgM/ IgG antibodies to either EBP2 or DEKnull-2, IgG antibodies against DEKnull-2 (but not EBP2) were boosted by recurrent blood-stage infections following treatment. Of interest, in most recurrent P. vivax infections (4 out of 6 patients) DEKnull-2 IgG antibodies were sustained for 6 to 12 months. Polymorphisms in the ebp2 gene does not seem to explain EBP2 low immunogenicity as the ebp2 allele associated with the P.vivax outbreak presented high identity to the original EBP2 isolate used as recombinant protein. Although EBP2 antibodies were barely detectable after a primary episode of P.vivax infection, EBP2 was highly recognized by serum IgG from long-term malaria-exposed Amazonians (range from 35 to 92% according to previous malaria episodes). Taken together, the results showed that individuals with a single and brief exposure to P.vivax infection develop very low anti-EBP2 antibodies, which tend to increase after long-term malaria exposure. Finally, the findings highlighted the potential of DEKnull-2 as a vaccine candidate, as in non-immune individuals anti-DEKnull-2 IgG antibodies were boosted even after a brief exposure to P.vivax blood stages.


Subject(s)
Malaria, Vivax , Malaria , Antibodies, Protozoan , Antibody Formation , Antigens, Protozoan/genetics , Cross-Sectional Studies , Humans , Immunoglobulin G , Immunoglobulin M , Malaria, Vivax/parasitology , Plasmodium vivax/genetics , Protozoan Proteins/genetics , Receptors, Cell Surface/genetics
13.
J Mol Neurosci ; 72(3): 633-641, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34822110

ABSTRACT

The Group 3 Medulloblastoma (Grp3-MB) is an aggressive molecular subtype with a high incidence of metastasis and deaths. In this study, were used an RNA sequencing data (RNA-Seq) from a Brazilian cohort of MBs to identify hub genes associated with the metastatic risk. Data validation were performed by using multiple large datasets from MBs (GSE85217, GSE37418, and EGAS00001001953). DESeq2 package in R software was used to identify the differentially expressed genes (DEGs) in our RNA-Seq data. The DEGs data were accessed to construct the modules/graphs of co-expression and to identify hub genes through Cytoscape platform. The coregulated genes were enriched by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and the protein-protein interaction (PPI) network was visualized by Cytoscape. The Kaplan-Meier plotter and ROC curves were used to validate the diagnostic and prognostic values of specific biomarkers identified through this model. We identified that inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as a downregulated hub gene, with a high diagnostic accuracy to Grp3-MBs and associated with tumor metastasis. In addition, we identified genes significantly correlated with ITPR1 that were associated with metastasis in Grp3-MB (ATP1A2, MTTL7A, and RGL1) and worst overall survival in MBs (ANTXR1 and RGL1). Our findings suggest that the ITPR1 hub gene is potentially involved in the metastatic process for Grp3-MB. Our data also provide evidence of targets that may serve as prognostic predictors and/or regulators for the metastatic process that maybe explored for further research of individualized therapy to Grp3-MBs.


Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cerebellar Neoplasms/genetics , Computational Biology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Humans , Inositol , Inositol 1,4,5-Trisphosphate Receptors/genetics , Inositol 1,4,5-Trisphosphate Receptors/metabolism , Medulloblastoma/genetics , Microfilament Proteins/metabolism , Prognosis , Receptors, Cell Surface/genetics
14.
Front Immunol ; 12: 779534, 2021.
Article in English | MEDLINE | ID: mdl-34970264

ABSTRACT

This is a case series study to evaluate immunological markers associated with schistosomiasis advanced fibrosis, including 69 patients from an endemic area from the State of Sergipe and from the Hepatology Service of the University Hospital in Sergipe, Brazil. Hepatic fibrosis was classified based on Niamey protocol for ultrasonography (US). Immune response to Schistosoma mansoni antigens was evaluated by stimulating peripheral blood mononuclear cells (PBMCs) from these patients with either adult worm (SWAP-10 µg/ml) or egg (SEA-10 µg/ml) antigens or purified protein derivative of turberculin (PPD-10 µg/ml) or phytohemagglutinin (PHA-1 µg/ml) for 72 h. The levels of IFN-γ, TNF-α, IL-5, IL-10, and IL-17 were measured in these supernatants by ELISA and IL-9 by Luminex. Single nucleotide polymorphisms in IL-17, IL10, and CD209 genes were genotyped using TaqMan probe by qPCR. Higher levels of IL-9, IL-10, and IL-17 were found in PBMC supernatants of patients with advanced hepatic fibrosis. Direct correlations were detected between IL-9 and IL-17 levels with US spleen sizes, portal vein diameters, and periportal thickening. The CD209 rs2287886 AG polymorphism patients produce higher IL-17 levels. Together, these data suggest a role of these cytokines in the immunopathogenesis of advanced fibrosis in human schistosomiasis.


Subject(s)
Antigens, Helminth/immunology , Interleukin-10/metabolism , Interleukin-17/metabolism , Interleukin-9/metabolism , Leukocytes, Mononuclear/metabolism , Liver Cirrhosis/blood , Schistosoma mansoni/immunology , Schistosomiasis mansoni/blood , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Biomarkers/metabolism , Case-Control Studies , Cell Adhesion Molecules/genetics , Cells, Cultured , Child , Female , Host-Parasite Interactions , Humans , Interleukin-10/genetics , Interleukin-17/genetics , Lectins, C-Type/genetics , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/parasitology , Liver Cirrhosis/immunology , Liver Cirrhosis/parasitology , Male , Middle Aged , Polymorphism, Single Nucleotide , Receptors, Cell Surface/genetics , Schistosoma mansoni/pathogenicity , Schistosomiasis mansoni/genetics , Schistosomiasis mansoni/immunology , Schistosomiasis mansoni/parasitology , Young Adult
15.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: mdl-34681866

ABSTRACT

A close connection between inflammation and the risk of developing colon cancer has been suggested in the last few years. It has been estimated that patients diagnosed with some types of inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, have up to a 30% increased risk of developing colon cancer. However, there is also evidence showing that the activation of anti-inflammatory pathways, such as the IL-4 receptor-mediated pathway, may favor the development of colon tumors. Using an experimental model of colitis-associated colon cancer (CAC), we found that the decrease in tumor development in global IL4Rα knockout mice (IL4RαKO) was apparently associated with an inflammatory response mediated by the infiltration of M1 macrophages (F480+TLR2+STAT1+) and iNOS expression in colon tissue. However, when we developed mice with a specific deletion of IL4Rα in macrophages (LysMcreIL4Rα-/lox mice) and subjected them to CAC, it was found that despite presenting a large infiltration of M1 macrophages into the colon, these mice were as susceptible to colon-tumorigenesis as WT mice. These data suggest that in the tumor microenvironment the absence of IL4Rα expression on macrophages, as well as the recruitment of M1 macrophages, may not be directly associated with resistance to developing colon tumors. Therefore, it is possible that IL4Rα expression in other cell types, such as colonic epithelial cells, could have an important role in promoting the development of colitis-associated colon tumorigenesis.


Subject(s)
Colitis/pathology , Colonic Neoplasms/pathology , Macrophages/pathology , Receptors, Cell Surface/genetics , Animals , Colonic Neoplasms/etiology , Colonic Neoplasms/genetics , Cytokines/metabolism , Female , Macrophages/physiology , Mice, Inbred BALB C , Mice, Knockout , Mice, Transgenic , Neoplasms, Experimental , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Receptors, Cell Surface/metabolism , Tumor-Associated Macrophages/pathology
16.
Sci Rep ; 11(1): 15956, 2021 08 05.
Article in English | MEDLINE | ID: mdl-34354186

ABSTRACT

The soybean technology MON 87701 × MON 89788, expressing Cry1Ac and conferring tolerance to glyphosate, has been widely adopted in Brazil since 2013. However, pest shifts or resistance evolution could reduce the benefits of this technology. To assess Cry1Ac soybean performance and understand the composition of lepidopteran pest species attacking soybeans, we implemented large-scale sampling of larvae on commercial soybean fields during the 2019 and 2020 crop seasons to compare with data collected prior to the introduction of Cry1Ac soybeans. Chrysodeixis includens was the main lepidopteran pest in non-Bt fields. More than 98% of larvae found in Cry1Ac soybean were Spodoptera spp., although the numbers of Spodoptera were similar between Cry1Ac soybean and non-Bt fields. Cry1Ac soybean provided a high level of protection against Anticarsia gemmatalis, C. includens, Chloridea virescens and Helicoverpa spp. Significant reductions in insecticide sprays for lepidopteran control in soybean were observed from 2012 to 2019. Our study showed that C. includens and A. gemmatalis continue to be primary lepidopteran pests of soybean in Brazil and that Cry1Ac soybean continues to effectively manage the target lepidopteran pests. However, there was an increase in the relative abundance of non-target Spodoptera spp. larvae in both non-Bt and Cry1Ac soybeans.


Subject(s)
Glycine max/genetics , Lepidoptera/genetics , Pest Control, Biological/methods , Animals , Bacillus thuringiensis Toxins/genetics , Bacterial Proteins/genetics , Brazil , Endotoxins/metabolism , Hemolysin Proteins/genetics , Insect Proteins/genetics , Insect Proteins/metabolism , Insecticides , Larva/drug effects , Lepidoptera/pathogenicity , Moths/drug effects , Plants, Genetically Modified/genetics , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism
17.
PLoS One ; 16(3): e0247658, 2021.
Article in English | MEDLINE | ID: mdl-33667240

ABSTRACT

Microsporidia are recognized as opportunistic pathogens in individuals with immunodeficiencies, especially related to T cells. Although the activity of CD8+ T lymphocytes is essential to eliminate these pathogens, earlier studies have shown significant participation of macrophages at the beginning of the infection. Macrophages and other innate immunity cells play a critical role in activating the acquired immunity. After programmed cell death, the cell fragments or apoptotic bodies are cleared by phagocytic cells, a phenomenon known as efferocytosis. This process has been recognized as a way of evading immunity by intracellular pathogens. The present study evaluated the impact of efferocytosis of apoptotic cells either infected or not on macrophages and subsequently challenged with Encephalitozoon cuniculi microsporidia. Macrophages were obtained from the bone marrow monocytes from C57BL mice, pre-incubated with apoptotic Jurkat cells (ACs), and were further challenged with E. cuniculi spores. The same procedures were performed using the previously infected Jurkat cells (IACs) and challenged with E. cuniculi spores before macrophage pre-incubation. The average number of spores internalized by macrophages in phagocytosis was counted. Macrophage expression of CD40, CD206, CD80, CD86, and MHCII, as well as the cytokines released in the culture supernatants, was measured by flow cytometry. The ultrastructural study was performed to analyze the multiplication types of pathogens. Macrophages pre-incubated with ACs and challenged with E. cuniculi showed a higher percentage of phagocytosis and an average number of internalized spores. Moreover, the presence of stages of multiplication of the pathogen inside the macrophages, particularly after efferocytosis of infected apoptotic bodies, was observed. In addition, pre-incubation with ACs or IACs and/or challenge with the pathogen decreased the viability of macrophages, reflected as high percentages of apoptosis. The marked expression of CD206 and the release of large amounts of IL-10 and IL-6 indicated the polarization of macrophages to an M2 profile, compatible with efferocytosis and favorable for pathogen development. We concluded that the pathogen favored efferocytosis and polarized the macrophages to an M2 profile, allowing the survival and multiplication of E. cuniculi inside the macrophages and explaining the possibility of macrophages acting as Trojan horses in microsporidiosis.


Subject(s)
Apoptosis/genetics , Encephalitozoon cuniculi/immunology , Immune Evasion , Macrophages/microbiology , Spores, Fungal/immunology , Animals , Bone Marrow/immunology , Bone Marrow/microbiology , Cell Differentiation , Coculture Techniques , Encephalitozoon cuniculi/genetics , Encephalitozoon cuniculi/growth & development , Female , Gene Expression , Humans , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Jurkat Cells , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Macrophages/immunology , Mannose Receptor , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/immunology , Mice , Mice, Inbred C57BL , Phagocytosis , Primary Cell Culture , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Spores, Fungal/genetics , Spores, Fungal/growth & development
18.
J Infect Dis ; 223(2): 278-286, 2021 02 03.
Article in English | MEDLINE | ID: mdl-33535235

ABSTRACT

BACKGROUND: Chikungunya infections range from subclinical infection to debilitating arthralgia and to chronic inflammatory rheumatism. Tumor necrosis factor (TNF) α, DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin), Toll-like receptor (TLR) 3, and blood groups have been directly or indirectly implicated in the susceptibility and pathogenesis of chikungunya. METHODS: To test the hypothesis that polymorphisms in genes coding for these molecules determine clinical outcomes of chikungunya infection, a retrospective case-control study was performed in León, Nicaragua. The study included 132 case patients and 132 controls, matched for age, sex and neighborhood. Case patients had clinical symptoms of chikungunya, which was diagnosed by means of polymerase chain reaction. Controls were individuals not reporting abrupt presentation of clinical chikungunya-like symptoms. Polymorphisms were identified by TaqMan single-nucleotide polymorphism genotyping assays. RESULTS: After adjustment for sociodemographic risk factors, chikungunya disease was associated with polymorphism in DC-SIGN and TLR3 genes (odds ratios, 5.2 and 3.3, respectively), and TNF-α with reduced persistent joint pain (0.24). Persistent joint pain was also associated with age, female sex and other comorbid conditions. Most interestingly, the Lewis-negative phenotype was strongly associated with both symptomatic chikungunya and immunoglobulin G seropositivity (odds ratios, 2.7, and 3.3, respectively). CONCLUSION: This study identified polymorphisms in DC-SIGN, TLR3, and TNF-α genes as well as Lewis-negative phenotype as risk factors for chikungunya infection and disease progression.


Subject(s)
Cell Adhesion Molecules/genetics , Chikungunya Fever/epidemiology , Chikungunya Fever/etiology , Genetic Predisposition to Disease , Lectins, C-Type/genetics , Polymorphism, Single Nucleotide , Receptors, Cell Surface/genetics , Toll-Like Receptor 3/genetics , Tumor Necrosis Factor-alpha/genetics , Case-Control Studies , Chikungunya Fever/diagnosis , Genetic Association Studies , Genotype , Humans , Nicaragua/epidemiology , Phenotype , Risk Assessment , Risk Factors
19.
PLoS Negl Trop Dis ; 15(2): e0009171, 2021 02.
Article in English | MEDLINE | ID: mdl-33617596

ABSTRACT

Brucella abortus is a Gram-negative bacterium responsible for a worldwide zoonotic infection-Brucellosis, which has been associated with high morbidity rate in humans and severe economic losses in infected livestock. The natural route of infection is through oral and nasal mucosa but the invasion process through host gut mucosa is yet to be understood. Studies have examined the role of NLRP6 (NOD-like receptor family pyrin domain-containing-6 protein) in gut homeostasis and defense against pathogens. Here, we investigated the impact of gut microbiota and NLRP6 in a murine model of Ba oral infection. Nlrp6-/- and wild-type (WT) mice were infected by oral gavage with Ba and tissues samples were collected at different time points. Our results suggest that Ba oral infection leads to significant alterations in gut microbiota. Moreover, Nlrp6-/- mice were more resistant to infection, with decreased CFU in the liver and reduction in gut permeability when compared to the control group. Fecal microbiota transplantation from WT and Nlrp6-/- into germ-free mice reflected the gut permeability phenotype from the donors. Additionally, depletion of gut microbiota by broad-spectrum-antibiotic treatment prevented Ba replication in WT while favoring bacterial growth in Nlrp6-/-. Finally, we observed higher eosinophils in the gut and leukocytes in the blood of infected Nlrp6-/- compared to WT-infected mice, which might be associated to the Nlrp6-/- resistance phenotype. Altogether, these results indicated that gut microbiota composition is the major factor involved in the initial stages of pathogen host replication and partially also by the resistance phenotype observed in Nlrp6 -/- mice regulating host inflammation against Ba infection.


Subject(s)
Brucellosis/physiopathology , Gastrointestinal Microbiome/physiology , Intestines/microbiology , Intestines/physiopathology , Administration, Oral , Animals , Anti-Bacterial Agents/administration & dosage , Brucella abortus , Brucellosis/microbiology , Fecal Microbiota Transplantation , Host-Pathogen Interactions , Mice , Mice, Inbred C57BL , Mice, Knockout , Permeability , Receptors, Cell Surface/genetics , Specific Pathogen-Free Organisms
20.
Viruses ; 13(1)2021 Jan 12.
Article in English | MEDLINE | ID: mdl-33445752

ABSTRACT

The yellow fever vaccine (YF17DD) is highly effective with a single injection conferring protection for at least 10 years. The YF17DD induces polyvalent responses, with a TH1/TH2 CD4+ profile, robust T CD8+ responses, and synthesis of interferon-gamma (IFN-γ), culminating in high titers of neutralizing antibodies. Furthermore, C-type lectin domain containing 5A (CLEC5A) has been implicated in innate outcomes in other flaviviral infections. Here, we conducted a follow-up study in volunteers immunized with YF17DD, investigating the humoral response, cellular phenotypes, gene expression, and single nucleotide polymorphisms (SNPs) of IFNG and CLEC5A, to clarify the role of these factors in early response after vaccination. Activation of CLEC5A+ monocytes occurred five days after vaccination (DAV). Following, seven DAV data showed activation of CD4+ and CD8+T cells together with early positive correlations between type II IFN and genes of innate antiviral response (STAT1, STAT2, IRF7, IRF9, OAS1, and RNASEL) as well as antibody levels. Furthermore, individuals with genotypes rs2430561 AT/AA, rs2069718 AG/AA (IFNG), and rs13237944 AC/AA (CLEC5A), exhibited higher expression of IFNG and CLEC5A, respectively. Together, we demonstrated that early IFN-γ and CLEC5A responses, associated with rs2430561, rs2069718, and rs13237944 genotypes, may be key mechanisms in the long-lasting immunity elicited by YF17DD.


Subject(s)
Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Immunity , Interferon-gamma/metabolism , Lectins, C-Type/genetics , Receptors, Cell Surface/genetics , Vaccination , Yellow Fever Vaccine/immunology , Yellow Fever/etiology , Yellow Fever/prevention & control , Adult , Animals , Female , Humans , Immunogenicity, Vaccine , Male , Middle Aged , Polymorphism, Genetic , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Young Adult
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