A5058900439- Research on Leishmaniasis Studies
- Ocular Surface and Contact Lens
- Trypanosoma species research and implications
- Corneal Surgery and Treatments
- Glaucoma and retinal disorders
- Endoplasmic Reticulum Stress and Disease
- Leptospirosis research and findings
- interferon and immune responses
- Carbohydrate Chemistry and Synthesis
- Viral Infections and Vectors
- Adenosine and Purinergic Signaling
- Alcohol Consumption and Health Effects
- Biochemical and Structural Characterization
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- NF-κB Signaling Pathways
- Lysosomal Storage Disorders Research
- Toxoplasma gondii Research Studies
- Insect Pest Control Strategies
- RNA regulation and disease
- Diet, Metabolism, and Disease
- CRISPR and Genetic Engineering
- Advanced Drug Delivery Systems
- Blood Coagulation and Thrombosis Mechanisms
- Salivary Gland Disorders and Functions
University of Virginia
2018-2024
Universidade Federal do Rio de Janeiro
2015-2019
Instituto de Biofísica Carlos Chagas Filho
2009-2018
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
2009-2018
Brigham and Women's Hospital
2017
Harvard University
2017
We investigated the type I interferon (IFN-1)/PKR axis in outcome of Leishmania (Leishmania) amazonensis infection, along with underlying mechanisms that trigger and sustain this signaling pathway. Reporter assays cell extracts from RAW-264.7 macrophages infected L. (L.) or HEK-293T cells cotransfected TLR2 PKR promoter constructions were employed. Primary TLR2-knockout (KO) IFNR-KO mice infected, levels PKR, IFN-1, superoxide dismutase 1 (SOD1) transcript compared. Immunohistochemical...
Leishmania parasites infect macrophages, causing a wide spectrum of human diseases, from cutaneous to visceral forms. In search novel therapeutic targets, we performed comprehensive in vitro and ex vivo mapping the signaling pathways upstream downstream antioxidant transcription factor [nuclear erythroid 2-related 2 (Nrf2)] leishmaniasis (CL), by combining functional assays murine macrophages with systems biology analysis situ (skin biopsies) CL patient samples. First, show PKR pathway...
The evolution of Leishmania infection depends on the balance between microbicidal and suppressor macrophage functions. Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a classic antiviral protein, is able to regulate number signaling pathways We investigated possible role PKR in modulation infection. Our data demonstrated that amazonensis led activation increased levels. Consistently, macrophages from knockout 129Sv/Ev mice RAW-264.7 cells stably expressing dominant-negative...
Abstract Leishmania parasites utilize adaptive evasion mechanisms in infected macrophages to overcome host defenses and proliferate. We report here that the PERK/eIF2α/ATF4 signaling branch of integrated endoplasmic reticulum stress response (IERSR) is activated by this pathway important for amazonensis infection. Knocking down PERK or ATF4 expression inhibiting kinase activity diminished L . decreased NRF2 its nuclear translocation, reduced HO-1 increased nitric oxide production. Meanwhile,...
Endoplasmic reticulum (ER) stress triggers the integrated ER-stress response (IERSR) that ensures cellular survival of ER and represents a primordial form innate immunity. We investigated role IERSR duringLeishmania amazonensisinfection. Treatment RAW 264.7 infected macrophages with stress-inducing agent thapsigargin (TG; 1 μM) increasedL. amazonensisinfectivity in an IFN1-α receptor (IFNAR)-dependent manner. In Western blot assays, we showed thatL. amazonensisactivates inositol-requiring...
The induced expression of nitric oxide synthase (iNOS) controls the intracellular growth Leishmania in infected macrophages. Histones deacetylases (HDACs) negatively regulate gene through formation complexes containing transcription factors such as NF-κB p50/50. Herein, we demonstrated occupancy p50/p50_HDAC1 to iNOS promoter associated with reduced levels H3K9Ac. Remarkably, found increased HDAC1 L. amazonensis-infected upregulation was not major-infected parasite load knocked-down...
Leishmania amazonensis activates the NF-κB transcriptional repressor homodimer (p50/p50) and promotes nitric oxide synthase (iNOS) downregulation. We investigated role of PI3K/Akt in p50/p50 activation effect on iNOS expression L. infection. The increased occupancy promoter infected macrophages was observed we demonstrated that both induction downregulation depended activation. Importantly, intracellular growth parasite also impaired during signalling inhibition knocked-down for Akt 1...
Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2α) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2α, which couples cellular signals, including endoplasmic reticulum (ER) translation. We previously identified 1,3-diarylureas 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific activators of that trigger the eIF2α phosphorylation arm ER stress...
Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, light refracting and immunoprotective tear film on eyes would collapse. Premature collapse, coupled with chronic inflammation compromising visual acuity, is a hallmark dry eye disease affecting 7 to 10% individuals worldwide. Although collapse seems independent mutation (unlike newborn lung alveoli), selective proteome possible lipidome changes have been noted. These...
Visceral leishmaniasis is a deadly illness caused by Leishmania donovani that provokes liver and spleen inflammation tissue destruction. In cutaneous leishmaniasis, the protein of L. major, named inhibitor serine peptidases (ISP) 2, inactivates neutrophil elastase (NE) present at macrophage surface, resulting in blockade TLR4 activation, prevention TNF-α* IFN-β production, parasite survival. We report poor intracellular growth macrophages from knockout mice for NE (ela−/−), TLR4, or TLR2....
Protein synthesis has been a very rich target for developing drugs to control prokaryotic and eukaryotic pathogens. Despite the development of new drug formulations, treating human cutaneous visceral Leishmaniasis still needs significant improvements due considerable side effects low adherence associated with current treatment regimen. In this work, we show that di-substituted urea-derived compounds I-17 3m are effective in inhibiting promastigote growth different Leishmania species reducing...
The Integrated Endoplasmic Reticulum Stress Response (IERSR) is an evolutionarily conserved adaptive mechanism that ensures homeostasis and cellular survival in the presence of stress including nutrient deprivation, hypoxia, imbalance Ca+ homeostasis, toxins microbial infection. Three transmembrane proteins regulate integrated signaling pathways comprise IERSR, namely, IRE-1 activates XBP-1, pancreatic ER kinase (PERK) phosphorylates eukaryotic translation initiation factor 2 Transcription...
Some 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting eIF2 alpha subunit (eIF2α), we tested 25 analogs cHAUs against Trypanosoma cruzi, agent Chagas disease. One them (I-17) presented selectivity...
Viral coinfections can modulate the severity of parasitic diseases, such as human cutaneous leishmaniasis. Leishmania parasites infect thousands people worldwide and cause from single self-healing lesions to massive mucosal destructive lesions. The transmission vertebrates requires bite Phlebotomine sandflies, which also transmit Phlebovirus. We have demonstrated that infection triggers Endoplasmic stress (ER stress) response in infected macrophages. In present paper, we tested hypothesis ER...
Introduction Ocular tears refract 80% of light and are essential for epithelial homeostasis. 7% the world's population suffer from tear insufficiency associated with compromised visual acuity chronic ocular surface inflammation. Lacritin, a glycoprotein constituent tears, restores homeostasis in mouse dry eye model, human corneal cells (HCET) subjected to eye‐like IFN‐g TNF‐a stress. It does so by transiently stimulating autophagy restoring oxidative phosphorylation. Lacritin also promotes...