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Publicações Científicas e Culturais 23080
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The Clinical Features, Pathogenesis and Methotrexate Therapy of Chronic Chikungunya Arthritis
(Universidade Federal de Minas Gerais, 2019) José Kennedy Amaral; Peter Taylor; Mauro Martins Teixeira; Thomas Morrison; Robert Schoen
Chikungunya fever (CHIKF) is an emerging viral infection that has spread widely, along with its Aedes vectors, throughout the tropics and beyond, causing explosive epidemics of acute illness and persistent disabling arthritis. The rheumatic symptoms associated with chikungunya virus (CHIKV) infection include polyarthralgia, polyarthritis, morning stiffness, joint edema, and erythema. Chronic CHIK arthritis (CCA) often causes severe pain and associated disability. The pathogenesis of CCA is not well understood. Proposed hypotheses include the persistence of a low level of replicating virus in the joints, the persistence of viral RNA in the synovium, and the induction of autoimmunity. In this review, we describe the main hypotheses of CCA pathogenesis, some of which support methotrexate (MTX) treatment which has been shown to be effective in preliminary studies in CCA.
Probability of dengue transmission and propagation in a non-endemic temperate area: conceptual model and decision risk levels for early alert, prevention and control
(Universidade Federal de Minas Gerais, 2019) Cecilia de Almeida Marques Toledo; Maria Mercedes Bendati; Claudia Torres Codeço; Mauro Martins Teixeira
Background: Dengue viruses have spread rapidly across tropical regions of the world in recent decades. Today, dengue transmission is observed in the Americas, Southeast Asia, Western Pacific, Africa and in non-endemic areas of the USA and Europe. Dengue is responsible for 16% of travel-related febrile illnesses. Although most prevalent in tropical areas, risk maps indicate that subtropical regions are suitable for transmission. Dengue-control programs in these regions should focus on minimizing virus importation, community engagement, improved vector surveillance and control. Results: We developed a conceptual model for the probability of local introduction and propagation of dengue, comprising disease vulnerability and receptivity, in a temperate area, considering risk factors and social media indicators. Using a rich data set from a temperate area in the south of Brazil (where there is active surveillance of mosquitoes, viruses and human cases), we used a conceptual model as a framework to build two probabilistic models to estimate the probability of initiation and propagation of local dengue transmission. The final models estimated with good accuracy the probabilities of local transmission and propagation, with three and four weeks in advance, respectively. Vulnerability indicators (number of imported cases and dengue virus circulation in mosquitoes) and a receptivity indicator (vector abundance) could be optimally integrated with tweets and temperature data to estimate probability of early local dengue transmission. Conclusions: We demonstrated how vulnerability and receptivity indicators can be integrated into probabilistic models to estimate initiation and propagation of dengue transmission. The models successfully estimate disease risk in different scenarios and periods of the year. We propose a decision model with three different risk levels to assist in the planning of prevention and control measures in temperate regions at risk of dengue introduction.
Effectiveness of Ultra-Low Volume insecticide spraying to prevent dengue in a non-endemic metropolitan area of Brazil
(Universidade Federal de Minas Gerais, 2019) Giovanni Marini; Giorgio Guzzetta; Cecilia de Almeida Marques Toledo; Mauro Martins Teixeira; Roberto Rosà; Stefano Merler
Management of vector population is a commonly used method for mitigating transmission of mosquito-borne infections, but quantitative information on its practical public health impact is scarce. We study the effectiveness of Ultra-Low Volume (ULV) insecticide spraying in public spaces for preventing secondary dengue virus (DENV) cases in Porto Alegre, a non-endemic metropolitan area in Brazil. We developed a stochastic transmission model based on detailed entomological, epidemiological and population data, accounting for the geographical distribution of mosquitoes and humans in the study area and spatial transmission dynamics. The model was calibrated against the distribution of DENV cluster sizes previously estimated from the same geographical setting. We estimated a ULV-induced mortality of 40% for mosquitoes and found that the implemented control protocol avoided about 24% of symptomatic cases occurred in the area throughout the 2015–2016 epidemic season. Increasing the radius of treatment or the mortality of mosquitoes by treating gardens and/or indoor premises would greatly improve the result of control, but trade-offs with respect to increased efforts need to be carefully analyzed. We found a moderate effectiveness for ULV-spraying in public areas, mainly due to the limited ability of this strategy in effectively controlling the vector population. These results can be used to support the design of control strategies in low-incidence, non-endemic settings.
Plasminogen and the Plasminogen Receptor, Plg-RKT, Regulate Macrophage Phenotypic, and Functional Changes
(Universidade Federal de Minas Gerais, 2019) Juliana Priscila Vago; Michelle Amantea Sugimoto; Kátia Maciel Lima; Graziele Letícia Negreiros Lima; Nagyung Baik; Mauro Martins Teixeira; Mauro Perretti; Robert Parmer; Lindsey Anne Miles; Lirlândia Pires Sousa
Inflammation resolution is an active process that functions to restore tissue homeostasis. Clearance of apoptotic leukocytes by efferocytosis at inflammatory sites plays an important role in inflammation resolution and induces remarkable macrophage phenotypic and functional changes. Here, we investigated the effects of deletion of either plasminogen (Plg) or the Plg receptor, Plg-RKT, on the resolution of inflammation. In a murine model of pleurisy, the numbers of total mononuclear cells recruited to the pleural cavity were significantly decreased in both Plg−/− and Plg-RKT−/− mice, a response associated with decreased levels of the chemokine CCL2 in pleural exudates. Increased percentages of M1-like macrophages were determined in pleural lavages of Plg−/− and Plg-RKT−/− mice without significant changes in M2-like macrophage percentages. In vitro, Plg and plasmin (Pla) increased CD206/Arginase-1 expression and the levels of IL-10/TGF-β (M2 markers) while decreasing IFN/LPS-induced M1 markers in murine bone-marrow-derived macrophages (BMDMs) and human macrophages. Furthermore, IL4-induced M2-like polarization was defective in BMDMs from both Plg−/− and Plg-RKT−/− mice. Mechanistically, Plg and Pla induced transient STAT3 phosphorylation, which was decreased in Plg−/− and Plg-RKT−/− BMDMs after IL-4 or IL-10 stimulation. The extents of expression of CD206 and Annexin A1 (important for clearance of apoptotic cells) were reduced in Plg−/− and Plg-RKT−/− macrophage populations, which exhibited decreased phagocytosis of apoptotic neutrophils (efferocytosis) in vivo and in vitro. Taken together, these results suggest that Plg and its receptor, Plg-RKT, regulate macrophage polarization and efferocytosis, as key contributors to the resolution of inflammation.
The Inhibition of Phosphoinositide-3 Kinases Induce Resolution of Inflammation in a Gout Model
(Universidade Federal de Minas Gerais, 2019) Izabela Galvão; Celso Martins Queiroz Junior; Vivian Louise Soares de Oliveira; Vanessa Pinho; Emílio Hirsch; Mauro Martins Teixeira
Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes that are involved in many aspects of immune cell function. PI3Kγ and PI3Kδ are the major isoforms expressed in leukocytes. The role of PI3K isoforms in the resolution of inflammation is still poorly understood. Here, we investigated the contribution of PI3Kγ and PI3Kδ to the resolution of inflammation in a model of gout in mice. Methods and Results: Experiments were performed in wild-type male C57/Bl6 mice. Selective inhibitors of PI3K-γ (AS605240) or PI3Kδ (GSK045) were injected in the joint 12 h after injection of MSU crystals, hence at the peak of inflammation. Inhibition of either PI3K isoform decreased number of neutrophils that migrated in response to the injection of MSU crystals. This was associated with reduction of myeloperoxidase activity and IL-1β levels in periarticular tissues and reduction of histological score. Joint dysfunction, as seen by reduced mechanical hypernociception, was improved by treatment with either inhibitor. The decrease in neutrophil numbers was associated with enhanced apoptosis and efferocytosis of these cells. There was shortening of resolution intervals, suggesting inhibition of either isoform induced the resolution of neutrophilic inflammation. Blockade of PI3Kγ or PI3Kδ reduced Nuclear Factor kappa B (NF-κB) activation. A pan-PI3K inhibitor (CL27c) reduced inflammation induced by MSU crystals by a magnitude that was similar to that attained by the PI3Kγ or PI3Kδ selective inhibitors alone. Conclusion: Taken together, these results suggest that neutrophils can use PI3Kγ or PI3Kδ to remain in the cavity and blockade of either isoenzyme is sufficient to induce their apoptosis and resolve inflammation in a murine model of gout.

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